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Osteoporosis

• A 67-year-old woman presents to the emergency department after falling while walking down the stairs of her home. She landed on her rear on a carpeted floor and denies hitting her head. She experienced severe pain in her right hip after the fall and is unable to bear weight on the affected side. Menopause began 17 years ago. She has smoked 1-pack of cigarettes for the past 40 years. On physical exam, her right leg is shortened, adducted, and externally rotated. Laboratory testing is unremarkable.
• decreased bone mass (osteopenia) that significantly increases the patient's risk of fracture
• post-menopausal
• post-menopausal women
• being ≥ 65 years of age
• people of Caucasian and Asian descent
• poor physical activity
• vitamin D deficiency and poor calcium intake
• alcohol use disorder
• warfarin, lithium, proton pump inhibitors, and glucocorticoids
• hyperparathyroidism
• hyperthyroidism
• multiple myeloma
• malabsorption syndromes
• osteoblasts have their biosynthetic and proliferative ability reduced with age
• athletes have increased bone density
• decreased physical activity results in bone loss
• however, the rate of formation is less than resorption resulting in a net bone loss
• such as the vertebral bodies, leading to vertebral compression fractures
• there is trabecular and cortical bone loss
• fractures (e.g., vertberal and hip), otherwise, patients are typically asymptomatic
• may see loss in height
• all women ≥ 65 and all men ≥ 70 years of age
• smoking and sedentary lifestyles are risk factors
• T-score ≤ -2.5
• serum calcium, phosphorus, parathyroid hormone, and alkaline phosphatase are normal
• histologically normal; however, there is a decreased quantity of normal bone

• calcium and vitamin D supplementation
• strength training
• smoking cessation
• first-line for pharmacologic therapy in osteoporosis
• second line therapy for osteoporosis
• can cause hot flashes and venous thromboembolism
• does not cause endometrial hyperplasia or increase risk of breast cancer
• considered first-line in patients with a very high risk of fracture
• Generally good if detected early and appropriately managed

• Orthopedics
• - Osteoporosis

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• MB 1 Preclinical Medical Students
• MB 2/3 Clinical Medical Students
• ORTHO Orthopaedic Surgery

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Osteoporosis

• A 68-year-old woman presents to her primary care physician with lower back pain of acute onset. She denies any trauma to the spine or any radiation of pain. Her last menstrual period was when she was 51-years-old. On physical exam, she has tenderness to palpation at the level of L4-L5, as well as a loss of lumbar lordosis. A dual-energy x-ray absorptiometry (DEXA) scan reveals a T-score of -2.7.
• decreased bone mass (osteopenia) that significantly increases the patient's risk of fracture
• post-menopausal
• post-menopausal women
• being ≥ 65 years of age
• people of Caucasian and Asian descent
• poor physical activity
• vitamin D deficiency and poor calcium intake
• alcohol use disorder
• proton pump inhibitors
• glucocorticoids
• hyperparathyroidism
• hyperthyroidism
• multiple myeloma
• malabsorption syndromes
• higher body weight associated with higher bone density
• osteoblasts have their biosynthetic and proliferative ability reduced with age
• athletes have increased bone density
• decreased physical activity results in bone loss
• weight-bearing physical activity results in increased bone mass and protects against osteoporosis
• however, the rate of formation is less than resorption resulting in a net bone loss
• such as the vertebral bodies, leading to vertebral compression fractures
• there is trabecular and cortical bone loss
• generally good if detected early and appropriately managed
• fractures (e.g., vertberal and hip), otherwise, patients are typically asymptomatic
• may see loss in height
• all women ≥ 65 and all men ≥ 70 years of age
• T-score ≤ -2.5
• serum calcium, phosphorus, parathyroid hormone, and alkaline phosphatase are normal
• histologically normal; however, there is a decreased quantity of normal bone

• calcium and vitamin D supplementation
• strength training
• smoking cessation
• first-line for pharmacologic therapy in osteoporosis
• considered first-line in patients with a very high risk of fracture
• distal radius
• vertebral body
• proximal humerus

• - Osteoporosis

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Osteoporosis

A skeletal condition that usually affects postmenopausal women and the elderly population, in which the loss of bone mineral density leads to decreased bone strength and an increased susceptibility to fractures.

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Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people

• Open access
• Published: 20 March 2021
• Volume 33 , pages 759–773, ( 2021 )

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• J. Barnsley 1   na1 ,
• G. Buckland 1   na1 ,
• P. E. Chan 1   na1 ,
• A. Ong 1   na1 ,
• A. S. Ramos 1   na1 ,
• M. Baxter 1 ,
• F. Laskou 2 ,
• E. M. Dennison 2 ,
• C. Cooper 2 , 3 &
• Harnish P. Patel   ORCID: orcid.org/0000-0002-0081-1802 1 , 2 , 4 , 5  

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Osteoporosis, a common chronic metabolic bone disease is associated with considerable morbidity and mortality. As the prevalence of osteoporosis increases with age, a paralleled elevation in the rate of incident fragility fractures will be observed. This narrative review explores the origins of bone and considers physiological mechanisms involved in bone homeostasis relevant to management and treatment. Secondary causes of osteoporosis, as well as osteosarcopenia are discussed followed by an overview of the commonly used pharmacological treatments for osteoporosis in older people.

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Introduction

Osteoporosis, a disease characterised by low bone mass and microarchitectural deterioration of bone tissue is the most common chronic metabolic bone disease. Annually contributing to 8.9 million fractures worldwide as well as to reduced physical and psychological health, lower quality of life and shorter life expectancy, osteoporosis represents a major global health problem [ 1 , 2 , 3 ]. In the UK, over 300,000 patients present to hospitals with fractures associated with osteoporosis and this is associated with a high health care cost [ 4 ]. For example, In the year 2000, osteoporosis incurred an estimated £1.8 billion in UK health costs and is predicted to increase to £2.2 billion by 2025. The prevalence of osteoporosis increases with age and both older women and men are at higher risk of fractures associated with both osteopenia and osteoporosis. These commonly occur at the vertebrae, wrist, hip and pelvis following low energy transfer trauma such as falling from a standing height—termed fragility fractures. Octo- and nonagenarians bear the greatest burden of osteoporosis related fractures and consequent morbidity and mortality. For example, mortality rate can be up to 20% in the years following hip fracture. Specific morbidity includes disability, chronic pain, impaired function and loss of independence and risk of short- and longer-term institutionalisation.

To understand the mechanism by which osteoporosis develops and the treatment options available, an understanding of the development, structure and remodelling process of bone in addition to the effects of ageing, disease and drug treatments on bone is needed. In this narrative review, our aim is to explore bone physiology and homeostasis, pathology and diagnosis of primary and secondary osteoporosis, osteosarcopenia and management of osteoporosis relevant to clinical practice.

Origins of bone, structure, function and differences in biological sex

During gastrulation, the blastula differentiates into three distinct cell lineages: the ectoderm, mesoderm and endoderm. At week four, the mesenchymal cells of the intraembryonic mesoderm divide into the three paired regions: paraxial mesoderm, intermediate mesoderm, and the lateral plate mesoderm [ 5 ]. The lateral plate mesoderm eventually forms the limb skeleton. The paraxial mesoderm segments into somites, which subdivide into sclerotomes, myotomes, syndetomes and dermatomes. The paraxial mesoderm hence gives rise to the muscles and axial skeleton [ 5 ]. The development of bone and muscle are intrinsically linked given their common embryonic origins (supplementary Fig.  1 ).

Remodelling cycle and regulators of bone formation. The bone remodelling cycle occurs in 5 stages—activation (during which osteoblastic expression of M-CSF and RANKL stimulate osteoclast progenitor maturation and differentiation into osteoclasts), resorption of bone (by osteoclasts), reversal, formation (new bone laid down by osteoblasts) and termination (bone returns to quiescent phase). Bone remodelling is stimulated by calcitriol and PTH and is inhibited during the quiescent phase by sclerostin, which inhibits WNT driven bone formation and OPG which inhibits RANK-RANKL interactions

Bone structure

Bone is a specialised and multifunctional connective tissue with both an organic and inorganic component. The organic bone matrix (osteoid) is comprised of collagenous proteins, the predominant being type I collagen [ 6 ] as well as a broad range of non-collagenous proteins including glycosaminoglycans, glycoproteins and some serum derived proteins. The numerous non-collagenous proteins regulate aspects of bone metabolism including deposition, mineralisation and turnover [ 7 ]. The inorganic component predominantly consists of calcium and phosphorus in the form of hydroxyapatite and provides mechanical rigidity to the bone and contributes to 50–70% of the overall total bone mass [ 6 ].

Of the two main types of bone in the adult skeleton, cortical comprises approximately 80% of adult bone mass and trabecular, the remaining 20%. Cortical bone is dense, has a low turnover rate of around 3% per year and maintains mechanical strength and integrity of the bone [ 6 , 8 ]. In contrast trabecular bone, found in long bones and vertebrae has a turnover rate of approximately 26% per year, has a lower mineralised content, is more metabolically active and responsive to hormonal stimuli [ 8 ]. Trabecular bone undergoes remodelling more than cortical bone; the clinical relevance is that fragility fractures typically occur in trabecular bone [ 8 ].

The cellular component of bone is chiefly composed of three cells: osteocytes, osteoblasts, and osteoclasts. Osteocytes are found in the lacunae of the matrix and have a mechano-sensory function in bone formation. Osteoblasts synthesize osteoid whilst osteoclasts enzymatically resorb bone [ 5 ]. All three subtypes are important for bone growth and remodelling throughout the lifecourse.

Bone homeostasis

Bone remodelling allows repair of micro-damage, maintaining skeletal structure as well as serum calcium and phosphate homeostasis and involves a careful equilibrium between the action of osteoclasts, tightly coupled with that of osteoblasts. Numerous clusters of these cells within multicellular units are found along the bone surface forming active remodelling sites which are individually covered by a cell canopy. This cell canopy has been found to be derived from mesenchymal stem cells (MSC) surrounding the red bone marrow and acts as a source of progenitor cells during the remodelling process [ 9 ]. A remodelling cycle on the resting bone surface occurs through five sequential stages: activation, resorption, reversal, formation and termination [ 10 ] (Fig.  1 ).

Activation of the resting bone surface is mediated by osteocytes that express an amino acid peptide; receptor activator of nuclear factor (NF) Kappa-B ligand (known commonly as RANKL), which interacts with the RANK receptor on osteoclast precursors that potently induces differentiation into multinucleated osteoclasts. Osteoblast expression of macrophage colony-stimulating factor (M-CSF) also promotes osteoclast precursor survival and differentiation. Osteoblasts produce chemokines, to recruit osteoclast precursors, and matrix metalloproteinases to degrade un-mineralised osteoid and expose adhesion sites for osteoclast attachment [ 11 , 12 , 13 ].

Osteoclasts secrete hydrogen ions and lysosomal enzymes, e.g., cathepsin-K into a ‘sealed zone’ beneath the cell [ 14 , 15 ]. Through acidification and proteolysis, they remove a tunnel of old bone. Osteoprotegerin (OPG) can block the RANK-RANKL interaction, thus reducing resorption by inhibiting osteoclast differentiation and increasing their apoptosis [ 11 ].

The reversal phase has been subject to intense research in recent years [ 16 , 17 ] and begins with osteoclastic signalling that persists for approximately 4 to 5 weeks [ 18 ] and is ultimately responsible for the crucial coupling of osteoclastic and osteoblastic activity seen at remodelling sites. ‘Reversal cells’ have long been recognised and although clearly distinct from osteoclasts and osteoblasts, their exact morphology and function is still uncertain [ 19 ].

Osteoblasts deposit un-mineralised osteoid until the tunnel of resorbed bone is completely replaced, resulting in minimal net change in bone volume during remodelling [ 20 ]. Bone formation is complete as osteoid is gradually mineralised through incorporation of hydroxyapatite. By the end of bone formation, approximately 10 to 15% of mature osteoblasts are entombed by the new bone matrix and differentiate into osteocytes. At rest osteocytes express sclerostin, which prevents WNT signalling (an inducer of bone formation) in osteoblasts [ 21 ]. Sclerostin expression is inhibited by parathyroid hormone (PTH) or mechanical stress, allowing wnt-induced bone formation to occur [ 12 ].

Termination

When the tunnel of resorbed bone has been fully replaced, the remodelling cycle ends through a series of yet undetermined termination signals. The resting bone surface is re-established.

Regulation of bone remodelling

Remodelling signals may be hormonal or mechanical in nature. Systemic regulators of bone formation include oestrogen, growth hormone and androgens. Thyroid hormones are essential for normal musculoskeletal development, maturation, metabolism, structure and strength where they promote bone turnover by influencing osteoblast and osteoclast activity [ 22 ]. Glucocorticoids prolong osteoclast survival and reduce bone formation by increasing osteoblast apoptosis [ 23 ]. Continuous high-dose parathyroid hormone (PTH) release induces bone resorption indirectly by promoting RANKL/MCSF expression and inhibiting OPG expression ( 14 ). Meanwhile, low intermittent PTH release induces bone formation by promoting increased survival, proliferation and differentiation of osteoblasts [ 24 ]. Other systemic regulators of bone remodelling include vitamin D3, calcitonin, insulin-like growth factor, prostaglandins and bone morphogenetic proteins. Local regulators of bone remodelling include cytokines, growth factors such as IGF-1, Sirtuins, protein kinases such as mechanistic target of rapamycin (mTOR), Forkhead proteins, M-CSF, wnt, sclerostin, and the RANK/RANKL/OPG system [ 12 , 24 ]. Bone remodelling is tightly controlled and alterations in cellular activity, i.e., increased osteoclastic activity in response to extrinsic or intrinsic cues will lead to increased bone resorption and decreased bone formation.

Bone volume and mass decline in older individuals and in all ethnicities. An imbalance in remodelling within the aged microenvironment is driven by MSC senescence and a shift in differentiation potential to favour adipogenesis within the bone marrow. An altered intracellular signalling milieu such as lower Sirtuin levels can lead to an increase in sclerostin activity, with inhibition of wnt and suppression of bone formation. Increased activity of mTOR translates to increased osteoclastic activity and release of cathepsin K [ 25 ].

Calcium and vitamin D homeostasis

Sufficient calcium supply is essential for bone mineralisation. Bone also acts as a calcium reservoir, restoring physiological homeostasis when serum levels are low through the action of PTH on bone resorption, renal calcium reabsorption and synthesis of active vitamin D [ 26 ]. Inactive vitamin D is hydroxylated first by 25-hydroxylase (CYP2R1) in the liver and is then converted to its active form, calcitriol (1,25[OH] 2 D 3 ), in the kidneys by 1a-hydroxylase (CYP27B1). PTH stimulates 1α-hydroxylase to increase levels of calcitriol. When serum calcium levels are normal or low, calcitriol acts on vitamin D receptors (VDRs) to increase intestinal and renal calcium uptake. However, when dietary calcium is insufficient to meet calcium demand, i.e., during periods of undernutrition often seen in older people, a negative calcium balance ensues. At this juncture, calcitriol inhibits bone mineralisation and enhances bone resorption through upregulation of RANKL expression. Through these actions, calcium and phosphate are mobilised from bone matrix to serum, at the expense of skeletal integrity. Calcitriol activation of osteocyte VDRs results in increased production of fibroblast growth factor 23 (FGF-23) which inhibits 1α-hydroxylase, thus creating a negative feedback system [ 27 ].

Peak bone mass and differences in biological sex

Peak bone mass is defined as the maximum amount of skeletal tissue an individual will have in their life at the termination of skeletal maturation. Peak bone mass is thought to be attained between 25 and 30 years of age thereafter decreasing at a rate of 0.5% per year [ 28 ]. Males attain a higher BMD, albeit later than females. The attainment of peak bone mass is a multifactorial process. The strongest evidence for peak bone mass appears to be genetically determined; up to 85% of the variation on peak bone mass can be explained by genetic factors, which in turn affects the physiological metabolism of bone [ 29 ]. It has been hypothesised that a rise in IGF-1 during puberty results in increased plasma inorganic phosphate and calcitriol, leading to increased bone mass gain during puberty. Patients with haploinsufficiency of IGF-1 receptor have been found to have undesirable changes to bone architecture in accordance with this hypothesis [ 30 , 31 ]. Other factors that can influence peak bone mass include nutrition (calcium and vitamin D status), physical activity, inter-current illness and socioeconomic deprivation.

• Osteoporosis

Bone loss is an inevitable consequence of ageing. Conditions which hinder an individual’s ability to maximise peak adult bone mass, increase the probability of developing osteoporosis and elevate fracture risk later in life. Primary osteoporosis can be categorised into age-related or post-menopausal. Women have an increased risk of primary osteoporosis, insofar as they reach a lower peak bone mineral density in comparison to men. This risk is further increased by the post-menopausal decline in oestrogen. However, it is important to note that approximately 20% of men with osteoporosis are hypogonadal.

Bone loss in women is most evident in the trabecular vertebral bodies as they are more metabolically active and are sensitive to the trophic effects of oestrogen which has a significant role in preventing bone resorption by inhibiting osteoclasts [ 32 ]. A steeper decline in bone mass begins approximately between 65 and 69 years in women and between 74 and 79 years in men [ 28 ]. Women aged 50 or over have a four-fold higher rate of osteoporosis and two-fold higher rate of osteopenia than men [ 2 ]. The lifetime risk of osteoporotic fractures in women is approximately 40% [ 33 ]. Weight loss in older people, smoking and moderate to high alcohol intake appear to accelerate the loss of bone in both men and women.

Secondary causes of osteoporosis relevant to older people

Several illnesses associated with osteoporosis are listed in Table 1 . A few of those illnesses and drug therapies pertinent to the development of osteoporosis in older people are discussed below. Further detailed discussion of secondary osteoporosis can be found in an excellent review [ 34 ].

Glucocorticoids

Glucocorticoids form part of the treatment strategy in a wide variety of diseases, including chronic inflammatory, rheumatological and respiratory illnesses. It is estimated that 1% of the population in the United Kingdom are receiving long term glucocorticoid therapy and the rate of long-term use is gradually increasing [ 35 ]. However, the anti-inflammatory therapeutic benefits are accompanied by adverse effects on bone health. It is estimated that vertebral and non-vertebral fractures occur in 30–40% of patients who are receiving chronic glucocorticoid therapy, and this effect appears to be dose dependent [ 36 ]. Nevertheless, fracture risk can rapidly return to baseline after steroid cessation. Glucocorticoids impair the function of osteoblasts, induce apoptosis of both osteoblasts and osteocytes and promote osteoclast formation ultimately leading to net suppression of bone formation [ 37 ]. The hormonal and intracellular effects of glucocorticoids are summarised in Fig.  2 .

Actions of glucocorticoid excess on bone

Proton pump inhibitors (PPI)

Long-term PPI prescriptions in the UK are increasing and their use have been associated with an elevated fracture risk [ 38 ]. Two main mechanisms are involved. Firstly, hypergastrinemia leads to osteoclastic precursor stimulation resulting in an alteration in balance that favours increased bone resorption. Secondly, hypochlorhydria affects the absorption of calcium and magnesium, leading to hyperparathyroidism and an increase in osteoclastic activity. There is an overall increase in fracture risk through the effects on bone remodelling, decreased mineral absorption as well as a decrease in muscle strength leading to poorer physical function and a higher falls risk [ 38 ].

Antiepileptic drugs (AED)

A systematic review and meta-analysis of 22 studies demonstrated that the use of AED is associated with an 86% increase in the risk of fractures at any site and a 90% increase in the risk of hip fractures [ 39 ]. This risk is higher in users of liver-enzyme inducing AED compared to non-enzyme inducing AED. Examples include phenobarbiturates, topiramate and phenytoin. Several theories are proposed to explain the effect of AED on bone metabolism. Predominantly, AED activate the orphan nuclear and pregnane-X receptors (PXR—expressed in the gut, kidneys and liver) and induce the cytochrome P450 enzyme system (CYP2, CYP3) leading to increased metabolism of vitamin D to inactive metabolites. Deficiency of vitamin D then causes hypocalcaemia and secondary hyperparathyroidism resulting in low bone mineral density and bone loss [ 40 ].

Systemic hormonal therapy

Aromatase inhibitors (AIs) used in the treatment of breast cancer can lead to increased bone loss and negative bone balance due to severe oestrogen depletion [ 41 ]. The increased bone loss from AI use compared to physiological postmenopausal bone loss is at least two fold [ 42 ]. Gonadotrophin Releasing hormone (GnRH) agonists bind to GnRH receptors in the pituitary and downregulate the gonadotropin-producing cells, limiting luteinizing hormone and follicle stimulating hormone secretion. Administration then leads to lower production of testosterone and oestradiol. Osteoblast, osteoclasts and osteocytes express androgen and oestrogen receptors and are responsive to both sex hormones. Reduction of these hormones leads to cellular dysfunction and affects bone remodelling by promoting bone resorption over formation [ 43 ].

Selective serotonin reuptake inhibitor (SSRI)

Osteoblasts and osteocytes harbour serotonin (5-hydroxytryptamine [5-HT]) receptors. 5-HT may have important signalling and regulatory roles in bone remodelling. SSRI use in women with a mean age of 78.5 years was associated with an increased rate of non-spine fractures [ 44 ]. In older men who took SSRI, a decrease of 3.9% in bone mineral density compared to those taking tricyclic antidepressants or none was observed [ 45 ]. The exact mechanisms of SSRI associated increase in fracture risk are currently still unclear. However, it is theorized that disruption of the serotonin receptors in bone cells could lead to altered signalling of bone formation pathways favouring bone resorption [ 46 ].

Thyroid disease

Hyperthyroidism can lead to higher bone turnover and osteoporosis. Both endogenous (primary thyroid disease) and exogenous causes, i.e., long term therapeutic use of levothyroxine as well as over-replacement with levothyroxine is associated with lower BMD and a subsequent increased risk of hip and vertebral fractures [ 22 , 34 , 47 ]. Hypothyroidism is associated with a slowing of bone formation and resorption and does not appear to increase fracture risk. However, subclinical hypothyroidism is associated with lower BMD and increased fracture risk in post-menopausal women [ 22 ].

Loop diuretics (LD)

LD are commonly prescribed and used in older people. Their diuretic activity centres around sodium and chloride reabsorption at the loop of Henle but they also decrease calcium reabsorption and increase calcium excretion. Hypocalcaemia can lead to increased bone turnover and lower BMD [ 48 ]. In clinical studies, use of LD was associated with lower hip BMD in men and higher fracture risk in post-menopausal women [ 49 ]. However, longer term studies and pragmatic RCTs are needed to study these effects as renal calcium loss may be offset by PTH dependent increase in active vitamin D activity to maintain normocalcaemia [ 50 ].

Chronic kidney disease (CKD)

The incidence of CKD increases in older age, but also in those who are hypertensive and have diabetes. CKD is associated with osteoporosis and renal osteodystrophy through perturbations in 1α-hydroxylation of vitamin D in the kidney, hypocalcaemia and hyperparathyroidism. Detailed discussion on renal bone disease is out of scope for this review. Several recent articles offer detailed reviews [ 51 ].

Both type 1 (T1DM) and type 2 (T2DM) diabetes are risk factors for low-energy fractures as both types are associated with low bone quality and strength, though only T1DM typically reduces BMD. T1DM is associated with increased risk of fracture throughout the lifecourse particularly at the hip [ 52 ], even when accounting for co-morbidities such as chronic kidney disease [ 53 ]. Fracture risk is hypothesised to be in part secondary to a deficiency in insulin and IGF-1, which are known to be important in determining peak bone mass [ 54 ]. T1DM commonly develops in adolescence and early adulthood. This represents a critical time to implement strategies to improve BMD and maximise peak bone mass.

T2DM is not associated with decreased BMD but is still associated with increased fracture risk at the hip, vertebrae and other vulnerable sites [ 52 ]. This presents a clinical challenge in older people insofar as the gold standard measurement of BMD may underestimate the true fracture risk for patients with T2DM. In fact, increased mechanical loading most often secondary to obesity and hormonal factors such as hyperinsulinemia, favour increasing deposition of bone [ 55 ]. As such, other mechanisms contribute to the increased fracture risk. For example, increased production of advanced glycation end-products in patients with chronic hyperglycaemia impair collagen cross-linking in the bone matrix, reducing bone quality and strength [ 56 ]. Patients with diabetes are also at higher risk of falling, attributable to factors such as peripheral neuropathy, lower physical function, orthostatic hypotension, poorer eyesight as well as hypoglycaemia from pharmacotherapy.

The coexistence of osteoporosis and sarcopenia—osteosarcopenia

Given bone and muscle share similar embryonic origins, both tissues may be influenced by similar metabolic (endocrine and paracrine) and environmental cues to maintain homeostasis. Sarcopenia (muscle failure) is characterised by a decline in skeletal muscle strength, mass and function [ 57 ]. Primary sarcopenia occurs with advancing age, whilst secondary sarcopenia is secondary to co-existent illnesses, e.g., diabetes. The prevalence of sarcopenia increases with age and similar to osteoporosis has a multifactorial aetiology—undernutrition, decreased physical activity, inflammation, presence of comorbid diseases. Diagnosis of sarcopenia involves measuring muscle strength (hand grip strength) and function (walking speed or chair rise time) [ 58 , 59 ], as well as lean mass—Dual-energy X-ray Absorptiometry (DXA) in this situation is a useful method to assess both total and appendicular lean mass as well as a bone mineral density for those suspected to have osteosarcopenia.

The pathophysiology of osteosarcopenia is multifactorial; the common mesenchymal origins of bone and muscle infer a close relationship in their pathogenesis [ 60 ]. As such, similar genetic factors can have a pleiotropic influence on both bone and muscle. Polymorphisms of several genes including androgen receptor, oestrogen receptor, IGF-1, and vitamin D receptor have been identified that can influence molecular cross talk and alter cellular mechanisms resulting in an imbalance in muscle and bone turnover [ 61 ]. The biomechanical relationship of muscle and bone is evident during ageing where lower physical activity and mechanical loading contributes to both decreased muscle mass, function and bone mineral density. This supports the ‘mechanostat hypothesis’, which postulates that if the mechanical forces of the skeletal musculature acting upon the periosteum reach a given threshold, growth is stimulated as opposed to bone resorbed [ 62 ]. In addition, as with caloric intake, dietary vitamin D and protein intake also diminishes with age, contributing to reduced muscle strength, lower bone mineralisation and an increase in falls risk [ 63 ]. Osteosarcopenia represents an additive burden for older people in terms of their physical and psychological health as well as their quality of life. Understanding the pathophysiology of osteosarcopenia is key to informing combined strategies for treatment and prevention.

Osteoporosis: diagnosis and management

The diagnosis of osteoporosis is made using DXA scanning to measure the bone mineral density (BMD) of the proximal femur to obtain a T-score. The T-score represents the number of standard deviations (SD) a patient’s BMD is below the mean reference value of a healthy young population. A T-score ≤ 2.5 SD below the reference value indicates osteoporosis [ 61 ] and where this is accompanied by one or more fractures, this indicates severe osteoporosis. However, the majority of fractures occur in individuals who are osteopenic, defined by a T-score of between 1.0 and 2.5 SDs below the mean reference value. These criteria, when combined with ascertainment of other risk factors and patient preferences inform appropriate lifestyle-management and treatment strategies. Interpretation of DXA results older people should be interpreted in context of the coexistence of degenerative spine disease, vertebral collapse, disc disease that can artificially elevate BMD. Conversely in osteomalacia, a complication of malnutrition in older people, lower total bone matrix and can lead to underestimation of BMD [ 64 ].

Assessment of risk

The UK National Institute for Health and Care Excellence (NICE) advise that all women aged 65 and above, all men aged 75 and above, and younger patients with risk factors should receive a form of osteoporosis risk assessment. The gold standard investigation for osteoporosis is bone mineral density (BMD). BMD at the femoral neck, age, sex, smoking, family history, and the use of oral glucocorticoids can be used to calculate the FRAX score. This tool estimates the 10-year probability of osteoporotic-related fracture [ 65 , 66 ]. The Trabecular Bone Score and QFracture are other assessment tools which have shown good predictive value [ 67 ]. All risk calculators generate a probability risk rather than indication for treatment. Whether in the community or within secondary care, management should be patient centred with treatment decisions based on shared decision making and what matters most for the patient with respect to patient preference, presence of comorbid diseases, i.e., CKD, consequent polypharmacy burden, social and psychological circumstances. It is worth noting that the FRAX score does not incorporate the dose-dependent effect of corticosteroids, alcohol and smoking on fracture risk nor the increased risk incurred by multiple prior fractures. These factors should be taken into account when assessing an older person’s individual fracture risk [ 64 ].

Screening and intervention for individuals who are high risk of fracture as a primary preventative endeavour could reduce the burden of future fragility fracture. For example, screening with FRAX and pharmacological intervention for post-menopausal women aged 70–85 at high risk developing a fracture was associated with a decrease in hip fracture rate and was deemed to be cost effective compared with usual care in the UK SCOOP study [ 68 ]. Older people presenting to secondary care with hip fracture are likely to be osteoporotic, sarcopenic, and also have several markers of frailty. As such their assessment and management should be multidisciplinary (orthopaedic, older people’s specialist teams, pharmacy, therapy, nursing, mental health, dietetics, speech and language) and be driven by the process of comprehensive geriatric assessment (CGA) [ 69 ]. Whilst this is the gold standard for patients presenting with a hip fracture, for less frail and more ambulant individuals presenting with other fragility fractures, i.e., wrist, shoulder and vertebral, fracture liaison services (FLS), which are typically multidisciplinary co-ordinated models of care systematically assess, identify and advise on risk factor management. They have a vital role in reducing the risk of subsequent, more debilitating fractures. Global Initiatives such as the International Osteoporosis Foundation’s Capture the Fracture initiative (capturethefracture.org) support the expansion of FLS within secondary care institutions. General principles include preserving bone mineral density, preserving muscle strength, and managing falls and other risk factors to maintain an individual’s independence.

Recently the concept of imminent fracture has been developed to highlight those most at risk of fracture within 2 years after a sentinel fracture. These events can occur in up to 23.2% of patients [ 70 ] and risk factors include recent fracture, fracture site, older age, osteoporosis and comorbidities, e.g., cognitive dysfunction, central nervous system polypharmacy, reduced physical activity, poorer general health as well as falls [ 71 , 72 ]. This supports the notion of early identification, assessment and treatment of those most at risk with the FLS model to reduce the future burden of fracture [ 73 ].

The diagnosis of sarcopenia relies on case finding through administering the SARC-F questionnaire or determining the presence of weaker grip strength through hand-held dynamometry or poorer performance in repeated chair rises. A probable case of sarcopenia identified at this stage allows multicomponent intervention with either nutritional or physical activity interventions. Measurement of lean mass through DXA and other measures of physical function such as gait speed can determine whether an individual has severe sarcopenia [ 59 ].

Non-pharmacological options for the treatment of osteoporosis

Research supports physical activity and exercise for the prevention of osteoporosis and related injury from falls and fractures [ 74 , 75 ]. In addition to preserving skeletal muscle, resistance exercise has also been shown to increase bone strength through repeated mechanical loading, thereby improving bone mineral density and reducing the development of osteoporosis [ 76 ]. For example, a systematic review of 43 randomised controlled trials and found the most effective type of exercise for increasing neck of femur bone mineral density was high force exercise, such as progressive resistance strength training of the lower limbs [ 77 ]. In addition, correcting biomechanical imbalance in the abdominal trunk as well as strengthening hip flexion and knee extension has been shown to reduce the risk of falls and alleviate musculoskeletal pain [ 78 , 79 , 80 ]. Furthermore, smoking cessation, avoiding alcohol excess, optimising dietary intake of calcium and consuming a balanced diet rich in fruit and vegetables, with a slant towards an increased protein intake are modifiable factors contributing to the prevention of osteoporosis [ 81 , 82 , 83 ]. In general, these principles can also apply to the management of sarcopenia and by reducing the risk of falls and subsequent fracture through improved bone mineral density, acute decompensation and progression of the frailty syndrome can be mitigated [ 84 , 85 ].

Pharmacological options for the treatment of osteoporosis

There are various pharmacological options for osteoporosis treatment that aim to reduce the risk of fractures. These include:

1. Calcium and vitamin D

2. Antiresorptive therapy—Bisphosphonates, Denosumab.

3. Hormonal treatment—Selective oestrogen receptor modulators, Testosterone, PTH analogues.

4. Novel therapies—Romosozumab, Dickkopf-1 (Dkk1) inhibitors.

1. Calcium and Vitamin D

Vitamin D deficiency in older people is common, not only secondary to physiological changes in the ability of the skin to synthesise vitamin D but particularly in those who are malnourished, have chronic kidney disease, are institutionalised or are housebound. National guidance recommends 1000 mg of calcium in combination with 400 International Units (IU) of vitamin D per day. Housebound older people or those living in a nursing home are advised to take 800 IU of vitamin D per day. A meta-analysis found that calcium and vitamin D supplementation reduced the risk of hip fracture by 30% and the total fracture risk by 15% [ 86 ]. This was supported by a study which found a 12% reduction in all fractures and a reduced rate of loss of BMD in the hip and spine in patients taking a minimum dose of 1200 mg calcium and 800 IU of vitamin D [ 87 ] (Table 2 ).

Evidence opposing the use of calcium supplementation suggests an increased risk of cardiovascular disease, including myocardial infarction [ 88 ]. However, other studies found no association between calcium supplementation and risk of cardiovascular disease [ 89 , 90 ]. Overall, there is insufficient evidence to outweigh the benefits from supplementation and current guidance recommends supplementation should be given to those with increased risk of insufficiency and individuals receiving treatment for osteoporosis. Calcium and vitamin D supplementation have also shown to have favourable effects on muscle health and the reduction in risk of falling [ 91 ].

2. Antiresorptive therapy—Bisphosphonates (Alendronate, risedronate, ibandronate and zolendronic acid)

Bisphosphonates bind strongly to hydroxyapatite, inhibit osteoclast-mediated bone resorption and increase bone mineral density. They are associated with beneficial effects on lowering the risk of fractures amongst a broad age range of patients; even those living with frailty [ 92 , 93 , 94 ]. Evidence shows 10 mg of alendronate daily for 10 years increased bone mineral density by 13.7% at the lumbar spine, 10.3% at the trochanter, 5.4% at the femoral neck, and 6.7% at the total proximal femur. Importantly, both oral and intravenous bisphosphonate therapy have shown to reduce the risk of mortality when commenced as secondary prevention measures after a fracture [ 93 , 94 , 95 , 96 ].

UK NICE guidance [ 97 ] recommends Alendronate 10 mg once daily or 70 mg once weekly; or Risedronate 5 mg once daily or 35 mg once weekly, for postmenopausal women and men over 50 years of age, who have confirmed osteoporosis on DXA. Evaluation of BMD usually occurs between 3 and 5 years. Thereafter, treatment is continued if the patient continues to be risk of fracture or has commenced on corticosteroid therapy. If the T-score is > − 2.5, a drug holiday may be recommended pending further evaluation of BMD and fracture risk. However, discontinuation of bisphosphonates in postmenopausal women at this time may be associated with up to 40% higher risk of new clinical fractures compared to those who continue bisphosphonates [ 98 ]. Ibandronic acid is not recommended first-line.

Adverse effects of oral bisphosphonates include gastrointestinal symptoms, bone/joint pain, oesophageal ulceration, and rarely osteonecrosis of the jaw (the highest risk is in patients with cancer). Atypical femoral fractures can occur particularly after 5 years of bisphosphonate use at the rate of 1:1000/year. Oral bisphosphonates should be taken on an empty stomach, in an upright position, with a glass of water [ 99 ]. Adherence to bisphosphonates may be challenging in older people because of this complex dosing regime and can be compounded by the presence of polypharmacy, impaired cognition and physical care needs. Furthermore, bisphosphonates are not stable to be kept in compliance aids. In older people with severe gastro-oesophageal reflux, dysphagia or cognitive impairment, alternative preparations, i.e., intravenous (IV) yearly Zoledronic acid or alternatives to bisphosphonates may be used [ 66 ]. Bisphosphonates are renally excreted and should be avoided in renal impairment. Estimated glomerular filtration rates (eGFR) provide thresholds to base treatment decisions upon. For example, alendronate and risedronate should be avoided when creatinine clearance is below 35 mL/min/1.73 m 2 and 30 mL/min/1.73 m 2 , respectively. However, eGFR may not be accurate in older people, especially those living with frailty and sarcopenia. Cockcroft and Gault estimation of GFR is, therefore, appropriate to use in these situations; especially when IV Zoledronic is being considered (Table 2 ).

Denosumab is a humanized monoclonal antibody that blocks RANKL and hence osteoclastic activity. It is given via a subcutaneous injection (60 mg)on a 6-monthly basis alongside calcium and vitamin D supplementation in individuals with a GFR > 30 ml/min/1.73 m 2 . FREEDOM (Fracture Reduction Evaluation of Denosumab), a large multicentre placebo-control trial showed a reduction in fracture incidence of 68% for vertebral fractures, 40% for hip fractures, and 20% for non-vertebral fractures, in the first 3 years, in postmenopausal woman taking Denosumab [ 100 ]; 10 year follow up showed continued decreasing fracture incidence and an increase in BMD without plateau [ 101 ]. Denosumab is often used as an alternative when oral bisphosphonates are not tolerated, are contraindicated or other social and psychological problems preclude bisphosphonate therapy. Treatment is usually for 5–10 years. The anti-resorptive effects of Denosumab rapidly diminishes after treatment cessation and consequently increase fracture risk back to pre-treatment levels within 12 months of cessation and therefore, requires both patient and physician led reminders on a 6-monthly basis. This is in contrast to bisphosphonates where BMD is maintained for at least 2 years after treatment withdrawal. Side effects include hypocalcaemia especially in individuals with impaired renal function, skin rash, increased risk of bacterial infections, osteonecrosis of the jaw and rarely, atypical femoral fractures (Table 2 ).

When initiating Denosumab or other anti-resorptive therapy, it is important to ensure that patients have normal serum calcium levels and are replete in vitamin D [ 66 ]. This lowers the risk of severe hypocalcaemia during treatment. Multiple loading regimes exist for those who are Vitamin D deficient. In the authors’ clinical practice, 100,000 IU of colecalciferol for individuals living with frailty and where rapid loading is needed appears to be well tolerated. Alternatives include 20,000 IU three times a week followed by 800 IU—1000 IU/day to maintain a serum vitamin D level above 50 nmol/L. Vitamin D in excess is associated with hypercalcemia, hypercalciuria and mineral deposits in soft tissues. However, doses of 800 IU to 1000 IU /day the for the prevention of Vitamin D deficiency is considered safe [ 102 ].

3. Hormonal treatment

Selective oestrogen receptor modulators (raloxifene and lasoxifene).

Selective oestrogen receptor modulators (SERMs) such as Raloxifene and Lasoxifene aim to prevent bone resorption due to oestrogen deficiency. They are indicated primarily for the treatment and prevention of osteoporosis in post-menopausal women and are indicated after first line therapies have been considered. As an example of efficacy, Lasoxifene 0.5 mg showed 42% reduction in vertebral fracture risk and 24% reduction in hazard rates of non-vertebral fractures, at 3 years in women aged 59–80 years [ 86 , 87 ]. Most common reported side effects include hot flushes and lower limb cramps. Increased risk of venous thromboembolism is the most severe adverse effect, though fortunately rare (Table 2 ).

Testosterone

Endocrine Society recommends testosterone for men at high risk for fracture with testosterone levels below 200 ng/dl (6.9 nmol/l). This should be considered even for patients who lack standard indications for testosterone therapy but who have contraindications to other osteoporosis’ therapies [ 103 ]. Potential side effects include cardiovascular and metabolic effects and rises in prostate specific antigen [ 104 ] (Table 2 ).

PTH analogues (Teriparatide, Abaloparatide)

Teriparatide, a synthetic parathyroid hormone, is anabolic in bone rather than anti-resorptive. It can be used in men and women who are intolerant or who suffer severe side effects from first line therapies described. Teriparatide should be administered subcutaneously, 20mcg daily for a maximum of 24 months. Teriparatide is contraindicated in patients with metabolic bone diseases such as Paget’s disease, skeletal muscle metastases or previous bone radiation therapy. Side effects include nausea, pain in limbs, headache and dizziness. Abaloparatide, a newer PTH analogue showed lower risks of new vertebral fractures when compared to both placebo and teriparatide as well as lower risk of nonvertebral fractures in comparison to placebo and a significant increase in BMD amongst 2463 post-menopausal women aged 49–86 years in the The ACTIVE study [ 105 ] (Table 2 ).

4. Novel therapies

Romosozumab.

Romosozumab is a monoclonal antibody that binds sclerostin leading to increased bone formation and a decrease in bone resorption. It is administered as a monthly subcutaneous injection, at a dose of 210 mg. The FRAME study was an international, randomized, double-blind, placebo-controlled trial that compared Romosozumab with placebo in postmenopausal women aged 55–90 with osteoporosis. Both groups also received denosumab 6 monthly. The Romosozumab treatment arm showed a 75% lower risk of new vertebral fractures, at 24 months; with no significant difference in adverse events [ 106 ].

The ARCH study, however, compared a group of postmenopausal women that received alendronate for 24 months and a group that received Romosozumab for 12 months followed by alendronate for another 12 months. Interestingly, patients on the Romosozumab-to-alendronate group had a 48% lower risk of new vertebral fractures ( p  < 0.001) and 27% lower risk of clinical fractures ( p  < 0.001). The risk of nonvertebral fractures was lower by 19% ( p  = 0.04) and the risk of hip fracture was lower by 38% ( p  = 0.02). Nonetheless, it is important to note an imbalance in serious cardiovascular adverse events between the 2 groups—16 patients (0.8%) in the Romosozumab group vs 6 (0.3%) in the alendronate group reported cardiac ischemic events (odds ratio 2.65; 95% CI 1.03–6.77); and 16 patients (0.8%) in the Romosozumab group vs 7 (0.3%) in the alendronate group reported cerebrovascular events (odds ratio 2.27; 95% CI 0.93–5.22). Further studies are needed to clarify this imbalance [ 107 ] (Table 2 ).

Dual inhibition of Dickkopf-1 (Dkk1) and sclerotin

Dkk1 is one of the antagonists in the Wnt signalling pathway which is an important cascade involved in bone formation. It was found that inhibition of sclerotin can lead to an upregulation of Dkk1 expression. Based on this, a study demonstrated the use of an engineered bio-specific antibody against sclerostin and Dkk1 simultaneously resulted in a bigger effect on bone formation compared to monotherapies in both rodents and primates. Improvements in healing and repair capacity of fractured bones were also seen when dual inhibition was used [ 108 ]. Results from clinical trials are currently awaited.

Treatments for osteosarcopenia

There are biochemical and hormonal relationships between bone and muscle through molecular cross-talk between myokines, osteokines and adipokines, secreted from muscle cells, bone cells and marrow adipose tissue, respectively. Abnormal expansion of marrow adipose tissue has been postulated to be a significant factor in the progression of post-menopausal osteoporosis [ 109 , 110 ]. Similarly, myosteatosis negatively impacts on muscle quality, the force generated per skeletal muscle unit area. Although no single molecule has been implicated in the pathogenesis of either condition, ongoing research may provide new targets for future therapy. Growth hormone, insulin-like growth factor-1, gonadal sex hormones, vitamin D and myostatin have all been associated with a delay in the onset of osteosarcopenia [ 111 ]. Though postulated to be novel therapeutic targets for drug development, currently no pharmacological treatments exist for osteosarcopenia [ 112 ].

Dementia and fragility fracture

Dementia increases with older age and is characterised by the presence of multimorbidity, cognitive and behavioural problems, visual and motor problems that consequently increase the risk of falls. Furthermore, high prevalence of malnutrition, frailty and sarcopenia in patients with dementia increases the likelihood of osteoporosis. This coexistence poses a particular therapeutic challenge, and an identified need exists for bone health measurement and pharmacological management in patients with dementia who are at high risk of incident and future fracture [ 113 ]. However, patents living with dementia are least likely to have their fracture risk assessed or receive longer term secondary prevention medications due to such reasons as delirium, worsening cognitive decline, institutionalisation, poor adherence and competing polypharmacy. In addition, altered pharmacokinetics conspire to risk adverse drug reactions (ADR) in this group of patients. In this regard, fracture risk undoubtedly increases commensurate with the incidence of dementia. CGA for such patients may just identify achievable goals to attain in the short and medium term when risks and benefits of treatment are considered in context of the wider social, physical and psychological domains [ 69 ].

Conclusions

The incidence of osteoporosis increases with age and the prevalence is increasing in line with global population ageing. Osteoporosis and sarcopenia often coexist and are associated with substantial burden for older people in terms of morbidity and mortality. Both are often underdiagnosed and undertreated. Routine assessment of bone and muscle health should be part of a holistic multidisciplinary led, personalised comprehensive geriatric assessment both in primary and secondary care. Nutrition, physical activity, exercise, gait and balance interventions have been shown to be beneficial for bone and muscle health and in reducing the number of falls. These should be instituted alongside other lifestyle measures as part of the treatment strategy for an older person.

Older people at risk of fracture derive considerable benefits from treatment with bone sparing agents; the choice should take into account frequency, route of administration, cost, potential for polypharmacy, ADR and long-term survival. In clinical practice bisphosphonates and denosumab; either first line or for older people intolerant to bisphosphonates, have a strong evidence base for efficacy in older people. For those intolerant or who are unable to have bone sparing agents, calcium and vitamin D should be offered to maintain bone health.

Compston J, Cooper A, Cooper C et al (2017) UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 12:43

CAS   PubMed   PubMed Central   Google Scholar  

Sözen T, Özışık L, Başaran N (2017) An overview and management of osteoporosis. Eur J Rheumatol 4:46–56

PubMed   Google Scholar  

Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17:1726–1733

CAS   PubMed   Google Scholar  

British Orthopaedic Association. The Care of Patients with Fragility Fracture (Blue Book). September 2007. https://www.bgs.org.uk/sites/default/files/content/attachment/2018-05-02/Blue%20Book%20on%20fragility%20fracture%20care.pdf

Olsen BR, Reginato AM, Wang W (2000) Bone development. Annu Rev Cell Dev Biol 16:191–220

Clarke B (2008) Normal bone anatomy and physiology. Clin J Am Soc Nephrol 3:S131–S139

Robey PG (1996) Vertebrate mineralized matrix proteins: structure and function. Connect Tissue Res 35:131–136

Oftadeh R, Perez-Viloria M, Villa-Camacho JC, Vaziri A, Nazarian A (2015) Biomechanics and mechanobiology of trabecular bone: a review. J Biomech Eng 137:0108021–01080215

PubMed Central   Google Scholar  

Kristensen HB, Andersen TL, Marcussen N et al (2014) Osteoblast recruitment routes in human cancellous bone remodeling. Am J Pathol 184:778–789

Katsimbri P (2017) Biology of normal bone remodelling. Eur J Cancer Care (Engl). https://doi.org/10.1111/ecc.12740

Article   Google Scholar  

Lacey DL, Timms E, Tan HL et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176

Raggatt LJ, Partridge NC (2010) Cellular and molecular mechanisms of bone remodeling. J Biol Chem 285:25103–25108

Tanaka S, Takahashi N, Udagawa N et al (1993) Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest 91:257–263

Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289:1504–1508

Väänänen HK, Zhao H, Mulari M et al (2000) The cell biology of osteoclast function. J Cell Sci 113:377–381

Delaisse JM (2014) The reversal phase of the bone-remodeling cycle: cellular prerequisites for coupling resorption and formation. Bonekey Rep 3:561

Sims NA, Martin TJ (2014) Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep 3:481

PubMed   PubMed Central   Google Scholar  

Eriksen EF, Melsen F, Mosekilde L (1984) Reconstruction of the resorptive site in iliac trabecular bone: a kinetic model for bone resorption in 20 normal individuals. Metab Bone Dis Relat Res 5:235–242

Van Tran P, Vignery A, Baron R (1982) An electron-microscopic study of the bone-remodeling sequence in the rat. Cell Tissue Res 225:283–292

Google Scholar  

Andersen TL, Sondergaard TE, Skorzynska KE et al (2009) A physical mechanism for coupling bone resorption and formation in adult human bone. Am J Pathol 174:239–247

Rochefort GY, Pallu S, Benhamou CL (2010) Osteocyte: the unrecognized side of bone tissue. Osteoporos Int 21:1457–1469

Delitala AP, Scuteri A, Doria C (2020) Thyroid hormone diseases and osteoporosis. J Clin Med 9:1034. https://doi.org/10.3390/jcm9041034

Article   CAS   PubMed Central   Google Scholar  

Weinstein RS (2011) Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med 365:62–70

Siddiqui JA, Partridge NC (2016) Physiological bone remodeling: systemic regulation and growth factor involvement. Physiol (Bethesda) 31:233–245

CAS   Google Scholar  

Roberts S, Colombier P, Sowman A et al (2016) Ageing in the musculoskeletal system. Acta Orthop 87:15–25

Goltzman D, Mannstadt M, Marcocci C (2018) Physiology of the calcium-parathyroid hormone-vitamin D axis. Front Horm Res 50:1–13

Christakos S, Dhawan P, Verstuyf A et al (2016) Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 96:365–408

Zanker J, Duque G (2019) Osteoporosis in older persons: old and new players. J Am Geriatr Soc 67:831–840

Bonjour JP, Theintz G, Law F et al (1994) Peak bone mass. Osteoporos Int 4:7–13

Pelosi P, Lapi E, Cavalli L et al (2017) Bone status in a patient with insulin-like growth factor-1 receptor deletion syndrome: bone quality and structure evaluation using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and quantitative ultrasonography. Front Endocrinol (Lausanne) 8:227

Yakar S, Rosen CJ, Beamer WG et al (2002) Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 110:771–781

Alswat KA (2017) Gender disparities in osteoporosis. J Clin Med Res 9:382–387

Lang TF (2011) The bone–muscle relationship in men and women. J Osteoporos 2011:702735

Mirza F, Canalis E (2015) Management of endocrine disease: secondary osteoporosis: pathophysiology and management. Eur J Endocrinol 173:R131–R151

Fardet L, Petersen I, Nazareth I (2011) Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. Rheumatol (Oxf) 50:1982–1990

Canalis E, Mazziotti G, Giustina A et al (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18:1319–1328

Hardy RS, Zhou H, Seibel MJ et al (2018) Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy. Endocr Rev 39:519–548

Thong BKS, Ima-Nirwana S, Chin KY (2019) Proton pump inhibitors and fracture risk: a review of current evidence and mechanisms involved. Int J Environ Res Public Health 16:1571

CAS   PubMed Central   Google Scholar  

Shen C, Chen F, Zhang Y et al (2014) Association between use of antiepileptic drugs and fracture risk: a systematic review and meta-analysis. Bone 64:246–253

Pascussi JM, Robert A, Nguyen M et al (2005) Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 115:177–186

Becker T, Lipscombe L, Narod S et al (2012) Systematic review of bone health in older women treated with aromatase inhibitors for early-stage breast cancer. J Am Geriatr Soc 60:1761–1767

Hadji P (2009) Aromatase inhibitor-associated bone loss in breast cancer patients is distinct from postmenopausal osteoporosis. Crit Rev Oncol Hematol 69:73–82

Mohamad NV, Soelaiman IN, Chin KY (2016) A concise review of testosterone and bone health. Clin Interv Aging 11:1317–1324

Diem SJ, Blackwell TL, Stone KL et al (2011) Use of antidepressant medications and risk of fracture in older women. Calcif Tissue Int 88:476–484

Haney EM, Chan BK, Diem SJ et al (2007) Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med 167:1246–1251

Bliziotes M (2010) Update in serotonin and bone. J Clin Endocrinol Metab 95:4124–4132

Vestergaard P, Mosekilde L (2002) Fractures in patients with hyperthyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients. Thyroid 12:411–419

Rejnmark L, Vestergaard P, Heickendorff L et al (2006) Loop diuretics increase bone turnover and decrease BMD in osteopenic postmenopausal women: results from a randomized controlled study with bumetanide. J Bone Miner Res 21:163–170

Lim LS, Fink HA, Blackwell T et al (2009) Loop diuretic use and rates of hip bone loss and risk of falls and fractures in older women. J Am Geriatr Soc 57:855–862

Rejnmark L, Vestergaard P, Heickendorff L et al (2005) Effects of long-term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover. J Intern Med 257:176–184

Miller PD (2014) Chronic kidney disease and osteoporosis: evaluation and management. Bonekey Rep 3:542

Bai J, Gao Q, Wang C et al (2020) Diabetes mellitus and risk of low-energy fracture: a meta-analysis. Aging Clin Exp Res 32:2173–2186

Weber DR, Haynes K, Leonard MB et al (2015) Type 1 diabetes is associated with an increased risk of fracture across the life span: a population-based cohort study using The Health Improvement Network (THIN). Diabetes Care 38:1913–1920

Fowlkes JL, Nyman JS, Bunn RC et al (2013) Osteo-promoting effects of insulin-like growth factor I (IGF-I) in a mouse model of type 1 diabetes. Bone 57:36–40

Felson DT, Zhang Y, Hannan MT et al (1993) Effects of weight and body mass index on bone mineral density in men and women: the Framingham study. J Bone Miner Res 8:567–573

Jackuliak P, Payer J (2014) Osteoporosis, fractures, and diabetes. Int J Endocrinol 2014:820615

Paintin J, Cooper C, Dennison E (2018) Osteosarcopenia. Br J Hosp Med (Lond) 79:253–258

Anker SD, Morley JE, von Haehling S (2016) Welcome to the ICD-10 code for sarcopenia. J Cachexia Sarcopenia Muscle 7:512–514

Cruz-Jentoft AJ, Bahat G, Bauer J et al (2019) Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48:16–31

Kaji H (2014) Interaction between muscle and bone. J Bone Metab 21:29–40

Karasik D, Kiel DP (2010) Evidence for pleiotropic factors in genetics of the musculoskeletal system. Bone 46:1226–1237

Frost HM (2003) Bone’s mechanostat: a 2003 update. Anat Rec A Discov Mol Cell Evol Biol 275:1081–1101

Marty E, Liu Y, Samuel A et al (2017) A review of sarcopenia: enhancing awareness of an increasingly prevalent disease. Bone 105:276–286

Kanis JA, Cooper C, Rizzoli R et al (2019) Executive summary of European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Aging Clin Exp Res 31:15–17

Kanis JA, Harvey NC, Johansson H et al (2020) A decade of FRAX: how has it changed the management of osteoporosis? Aging Clin Exp Res 32:187–196

Kanis JA, McCloskey EV, Johansson H et al (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 24:23–57

McCloskey EV, Odén A, Harvey NC et al (2016) A meta-analysis of trabecular bone score in fracture risk prediction and its relationship to FRAX. J Bone Miner Res 31:940–948

Shepstone L, Fordham R, Lenaghan E et al (2012) A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of screening older women for the prevention of fractures: rationale, design and methods for the SCOOP study. Osteoporos Int 23:2507–2515

Aggarwal P, Woolford SJ, Patel HP (2020) Multi-morbidity and polypharmacy in older people: challenges and opportunities for clinical practice. Geriatrics (Basel) 5:85

Hannan MT, Weycker D, McLean RR et al (2019) Predictors of imminent risk of nonvertebral fracture in older, high-risk women: the framingham osteoporosis study. JBMR Plus 3:e10129

Iconaru L, Moreau M, Baleanu F et al (2021) Risk factors for imminent fractures: a substudy of the FRISBEE cohort. Osteoporosis Int. https://doi.org/10.1007/s00198-020-05772-8

Yusuf AA, Hu Y, Chandler D et al (2020) Predictors of imminent risk of fracture in medicare-enrolled men and women. Arch Osteoporos 15:120

Pinedo-Villanueva R, Charokopou M, Toth E et al (2019) Imminent fracture risk assessments in the UK FLS setting: implications and challenges. Arch Osteoporos 14:12

de Labra C, Guimaraes-Pinheiro C, Maseda A, Lorenzo T, Millán-Calenti JC (2015) Effects of physical exercise interventions in frail older adults: a systematic review of randomized controlled trials. BMC Geriatr 15:154

Kujala UM, Kaprio J, Kannus P et al (2000) Physical activity and osteoporotic hip fracture risk in men. Arch Intern Med 160:705–708

Hong AR, Kim SW (2018) Effects of resistance exercise on bone health. Endocrinol Metab 33:435

Howe TE, Shea B, Dawson LJ, Downie F et al (2011) Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD000333

Article   PubMed   PubMed Central   Google Scholar  

Granacher U, Gollhofer A, Hortobágyi T et al (2013) The importance of trunk muscle strength for balance, functional performance, and fall prevention in seniors: a systematic review. Sports Med 43:627–641

Demarteau J, Jansen B, Van Keymolen B et al (2019) Trunk inclination and hip extension mobility, but not thoracic kyphosis angle, are related to 3D-accelerometry based gait alterations and increased fall-risk in older persons. Gait Posture 72:89–95

Demura T, Demura S-I, Uchiyama M et al (2014) Examination of factors affecting gait properties in healthy older adults. J Geriatr Phys Ther 37:52–57

Berg KM, Kunins HV, Jackson JL et al (2008) Association between alcohol consumption and both osteoporotic fracture and bone density. Am J Med 121:406–418

Cheraghi Z, Doosti-Irani A, Almasi-Hashiani A et al (2019) The effect of alcohol on osteoporosis: a systematic review and meta-analysis. Drug Alcohol Depend 197:197–202

Movassagh EZ, Vatanparast H (2017) Current evidence on the association of dietary patterns and bone health: a scoping review. Adv Nutr 8:1–16

Bauer J, Biolo G, Cederholm T et al (2013) Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE Study Group. J Am Med Dir Assoc 14:542–559

Woolford SJ, Sohan O, Dennison EM et al. (2020) Approaches to the diagnosis and prevention of frailty. Aging Clin Exp Res 32:1629–1637

Weaver CM, Alexander DD, Boushey CJ et al (2016) Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int 27:367–376

Tang BM, Eslick GD, Nowson C (2007) Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370:657–666

Harvey NC, Biver E, Kaufman JM et al (2017) The role of calcium supplementation in healthy musculoskeletal ageing : an expert consensus meeting of the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO) and the international foundation for osteoporosis (IOF). Osteoporos Int 28:447–462

Chung M, Tang AM, Fu Z et al (2016) Calcium intake and cardiovascular disease risk: an updated systematic review and meta-analysis. Ann Intern Med 165:856–866

Lewis JR, Radavelli-Bagatini S, Rejnmark L et al (2015) The effects of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: a collaborative meta-analysis of randomized controlled trials. J Bone Miner Res 30:165–175

Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB et al (2009) Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 339:b3692

Sanderson J, Martyn-St James M, Stevens J et al (2016) Clinical effectiveness of bisphosphonates for the prevention of fragility fractures: a systematic review and network meta-analysis. Bone 89:52–58

Vandenbroucke A, Luyten FP, Flamaing J (2017) Pharmacological treatment of osteoporosis in the oldest old. Clin Interv Aging 12:1065–1077

Zullo AR, Zhang T, Lee Y et al (2019) Effect of bisphosphonates on fracture outcomes among frail older adults. J Am Geriatr Soc 67:768–776

Beaupre LA, Morrish DW, Hanley DA et al (2011) Oral bisphosphonates are associated with reduced mortality after hip fracture. Osteoporos Int 22:983–991

Sambrook PN, Cameron ID, Chen JS et al (2011) Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study. Osteoporos Int 22:2551–2556

NICE (2020) NIfHaCE. Osteoporosis overview. 4 November 2020

Mignot MA, Taisne N, Legroux I et al (2017) Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk. Osteoporos Int 28:3431–3438

Tella SH, Gallagher JC (2014) Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol 142:155–170

Cummings SR, San Martin J, McClung MR et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765

Bone HG, Hosking D, Devogelaer JP et al (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199

Rizzoli R (2021) Vitamin D supplementation: upper limit for safety revisited? Aging Clin Exp Res 33:19–24. https://doi.org/10.1007/s40520-020-01678-x

Article   PubMed   Google Scholar  

Watts NB, Adler RA, Bilezikian JP et al (2012) Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97:1802–1822

Grech A, Breck J, Heidelbaugh J (2014) Adverse effects of testosterone replacement therapy: an update on the evidence and controversy. Ther Adv Drug Saf 5:190–200

Miller PD, Hattersley G, Riis BJ et al (2016) Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA 316:722–733

Cosman F, Crittenden DB, Adachi JD et al (2016) Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 375:1532–1543

Saag KG, Petersen J, Brandi ML et al (2017) Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 377:1417–1427

Florio M, Gunasekaran K, Stolina M et al (2016) A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun 7:11505

Herrmann M (2019) Marrow fat-secreted factors as biomarkers for osteoporosis. Curr Osteoporos Rep 17:429–437

Li J, Chen X, Lu L et al (2020) The relationship between bone marrow adipose tissue and bone metabolism in postmenopausal osteoporosis. Cytokine Growth Factor Rev 52:88–98

Girgis CM, Mokbel N, Digirolamo DJ (2014) Therapies for musculoskeletal disease: can we treat two birds with one stone? Curr Osteoporos Rep 12:142–153

Kirk B, Miller S, Zanker J et al (2020) A clinical guide to the pathophysiology, diagnosis and treatment of osteosarcopenia. Maturitas 140:27–33

Downey CL, Young A, Burton EF et al (2017) Dementia and osteoporosis in a geriatric population: Is there a common link? World J Orthop 8:412–423

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Acknowledgements

JB, GB, AO, PEC, ASR, MB and HPP are supported by the Department of Medicine for Older People, University Hospital Southampton, Southampton, UK. HPP and FL are supported by the NIHR Southampton Biomedical Research Centre, Nutrition and the University of Southampton. EMD and CC are supported by the MRC Lifecourse Epidemiology Centre. This report is independent research and the views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. These funding bodies had no role in writing of the manuscript or decision to submit for publication.

No funding was granted for this publication. This is an independent review from the authors as part of their clinical and medical roles within the UK National Health Service.

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J. Barnsley, G. Buckland, P.E. Chan, A. Ong and A.S. Ramos were equal contributors.

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Medicine for Older People, University Hospital Southampton NHS Foundation Trust, Southampton, UK

J. Barnsley, G. Buckland, P. E. Chan, A. Ong, A. S. Ramos, M. Baxter & Harnish P. Patel

MRC Lifecourse Epidemiology Centre, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK

F. Laskou, E. M. Dennison, C. Cooper & Harnish P. Patel

University of Oxford, Oxford, UK

Academic Geriatric Medicine, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

Harnish P. Patel

NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and The University of Southampton, Southampton, UK

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Barnsley, J., Buckland, G., Chan, P.E. et al. Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people. Aging Clin Exp Res 33 , 759–773 (2021). https://doi.org/10.1007/s40520-021-01817-y

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Biological causes of osteoporosis

In adults, the daily removal of small amounts of bone mineral, a process called resorption, is balanced by an equal deposition of new mineral in order to maintain bone strength. When this balance tips toward excessive resorption, bones weaken and over time can become brittle and prone to fracture (osteoporosis).

This continual resorption and re-deposition of bone mineral, or bone remodelling, is intimately tied to the pathophysiology of osteoporosis. Understanding how bone remodelling is regulated is the key to the effective prevention and treatment of osteoporosis.

Bones have evolved to be light yet strong. These properties are conferred to a large degree by architecture and geometry [2] Martin, R.M. and P.H. Correa, Bone quality and osteoporosis therapy . Arq Bras Endocrinol Metabol, 2010. 54 (2): p. 186-99. . The long bones are tubular in shape, with a strong outer shell, or cortical layer, surrounding a spongier core called trabecular bone [3] Parfitt, A.M., Chapter 15 - Skeletal Heterogeneity and the Purposes of Bone Remodeling: Implications for the Understanding of Osteoporosis, in Osteoporosis (Second Edition) , R. Marcus, D. Feldman, and J. Kelsey, Editors. 2001, Academic Press: San Diego. p. 433-447. . The combination makes these bones strong and light, but flexible enough to absorb the stress – from high impact exercises – without breaking. The vertebrae are similarly constructed, with a thick cortical layer surrounding sheets of trabecular bone. As a unit, each vertebra can compress when temporarily loaded and then return to their original size.

The influence of bone geometry on bone strength [2] Martin, R.M. and P.H. Correa, Bone quality and osteoporosis therapy . Arq Bras Endocrinol Metabol, 2010. 54 (2): p. 186-99. .

Left: for the same areal bmd, bone c has progressively greater bending strength and axial strength than bone b and bone a because the mass of bone c is distributed further away from the centre [1] bouxsein, m.l., determinants of skeletal fragility . best pract res clin rheumatol, 2005. 19 (6): p. 897-911. . right: sex and ageing differences in periosteal apposition and endocortical resorption in tubular bones [4] seeman, e., bone quality: the material and structural basis of bone strength . j bone miner metab, 2008. 26 (1): p. 1-8. .  .

However, a skeleton is alive and must be able to grow, heal, and respond to its environment. This is where bone remodelling plays a crucial role. However, as we age, daily remodelling leads to a gradual resorption of the minerals on the inside of the cortical layer and in the bone cavity itself leads to an inexorable loss of trabecular bone and a widening of the bone cavity. This is partly compensated for by the gradual addition of extra layers of mineral to the outside of the cortical layer [5] Seeman, E., From density to structure: growing up and growing old on the surfaces of bone . J Bone Miner Res, 1997. 12 (4): p. 509-21 .

Continual remodelling, and its effect on bone microarchitecture have a huge impact on the pathophysiology of osteoporosis. For example, young adults with wider femurs might be at higher risk for hip fractures late in life because, on average, wider bones tend to have thinner cortical layers. The thinner this layer is, the more susceptible it will be to resorption later in life [6] Seeman, E. and P.D. Delmas, Bone quality--the material and structural basis of bone strength and fragility . N Engl J Med, 2006. 354 (21): p. 2250-61 .

Figure taken from Ferrari & Roux, 2019 [7] Pocket Reference to Osteoporosis , S. Ferrari, Roux, C., Editor 2019, Springer International Publishing. . 

The cellular connection.

The balance between bone resorption and bone deposition is determined by the activities of two principle cell types, osteoclasts and osteoblasts, which are from two different origins. Osteoclasts are endowed with highly active ion channels in the cell membrane that pump protons into the extracellular space, thus lowering the pH in their own microenvironment [8] Blair, H.C., et al., Osteoclastic bone resorption by a polarized vacuolar proton pump . Science, 1989. 245 (4920): p. 855-7. . This drop in pH dissolves the bone mineral. They also produce in this microenvironment proteolytic enzymes, among them cathepsin K, which dissolve bone matrix. Osteoblasts, through a yet poorly characterized mechanism, lay down new bone mineral. The balance between the activities of these two cell types governs whether bone is made, maintained, or lost. The activities of these cells are also intimately intertwined. 

In a typical bone remodelling cycle, osteoclasts are activated first, leading to bone resorption (see bone biology – bone remodelling ) . Then, after a brief “reversal” phase, during which the resorption “pit” is occupied by osteoblasts precursors, bone formation begins as progressive waves of osteoblasts form and lay down fresh bone matrix [9] Orwoll, E.S., Toward an expanded understanding of the role of the periosteum in skeletal health . J Bone Miner Res, 2003. 18 (6): p. 949-54. . Because the bone formation phase typically takes much longer than the resorption phase, any increase in remodelling activity tends to result in a net loss of bone. At various stages throughout this process, the precursors, osteoclasts, and osteoblasts communicate with each other through the release of various “signalling” molecules [6] Seeman, E. and P.D. Delmas, Bone quality--the material and structural basis of bone strength and fragility . N Engl J Med, 2006. 354 (21): p. 2250-61 [10] Raisz, L.G., Pathogenesis of osteoporosis: concepts, conflicts, and prospects . J Clin Invest, 2005. 115 (12): p. 3318-25. . How these signalling molecules and various other endogenous (such as hormones) or external (such as diet and exercise) factors influence the cells involved in bone physiology is a topic of intense research activity.

Factors influencing osteoclasts and osteoblasts

Hormones are possibly the most crucial modulators of bone formation. It is well established that oestrogen [11] Lindsay, R., Prevention and treatment of osteoporosis . Lancet, 1993. 341 (8848): p. 801-5. . parathyroid hormone [12] Lips, P., Vitamin D physiology . Prog Biophys Mol Biol, 2006. 92 (1): p. 4-8 . and to a lesser extent testosterone directly or indirectly via the conversion into oestrogen [13] Seeman, E., The structural basis of bone fragility in men . Bone, 1999. 25 (1): p. 143-7. [14] Van Pottelbergh, I., et al., Perturbed sex steroid status in men with idiopathic osteoporosis and their sons . J Clin Endocrinol Metab, 2004. 89 (10): p. 4949-53. . are essential for optimal bone development and maintenance. Of these, oestrogen is now believed to have the most direct effect on bone cells, interacting with specific proteins, or receptors, on the surface of osteoblasts and osteoclasts [15] Zallone, A., Direct and indirect estrogen actions on osteoblasts and osteoclasts . Ann N Y Acad Sci, 2006. 1068 : p. 173-9 .

This interaction sets off a complex chain of events within the cells, increasing osteoblast activity while at the same time interfering with osteoblast-osteoclast communication – one of the ironies of bone remodelling is that the osteoblasts release factors that stimulate osteoclasts and drive bone resorption, as we shall see below.

Oestrogen effects are mediated through one specific type of cell surface receptor called the oestrogen receptor alpha (ERα), which binds and transports the hormone into the nucleus of the cell where the receptor-hormone complex acts as a switch to turn on specific genes. ERα receptors are found on the surface of osteoblasts, as is oestrogen receptor-related receptor alpha (ERRα), which may play an auxiliary role in regulating bone cells [16] Bonnelye, E. and J.E. Aubin, Estrogen receptor-related receptor alpha: a mediator of estrogen response in bone . J Clin Endocrinol Metab, 2005. 90 (5): p. 3115-21. . Recent studies also suggest that sex hormone binding globulin (SHBG), which facilitates entry of oestrogen into cells, may also play a supportive role [17] Goderie-Plomp, H.W., et al., Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study . J Clin Endocrinol Metab, 2004. 89 (7): p. 3261-9. .

Oestrogen, of course, is made and secreted into the bloodstream some distance from bone and it also has profound effects on other tissues, such as the uterus and breast. But there are other, locally produced signalling molecules that have profound effects on bone physiology.

Prostaglandins, particularly prostaglandin E2 (PGE2), stimulate both resorption and formation of bone [18] Pilbeam, C.C., J.R. Harrison, and L.G. Raisz, Chapter 54 - Prostaglandins and Bone Metabolism, in Principles of Bone Biology (Second Edition) , J.P. Bilezikian, L.G. Raisz, and G.A. Rodan, Editors. 2002, Academic Press: San Diego. p. 979-994 . PGE2 is a lipid that is formed in various bone cells from a precursor called arachidonic acid. The first step on PGE2 synthesis is carried out by an enzyme called cyclooxygenase 2 (COX2) and inhibitors of this enzyme can prevent bone formation in response to mechanical stress in animals [19] Forwood, M.R., Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo . J Bone Miner Res, 1996. 11 (11): p. 1688-93. . PGE2 may be required for exercise-induced bone formation.

There is evidence that fracture risk is increased in people taking non-steroidal anti-inflammatory drugs that inhibit COX-2 [20] Carbone, L.D., et al., Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: impact of cyclooxygenase selectivity. J Bone Miner Res, 2003. 18 (10): p. 1795-802 may also increase. Another set of lipid molecules that appear to regulate bone remodelling are the leukotrienes. Also derived from arachidonic acid, these have been found to reduce bone density in mice [21] Traianedes, K., et al., 5-Lipoxygenase metabolites inhibit bone formation in vitro . Endocrinology, 1998. 139 (7): p. 3178-84. .

How any of these hormones impact bone remodelling depends on how they alter osteoclasts and/or osteoblasts activity. Specific cell surface receptors help to transmit signals from outside bone cells into the cell nucleus, where different genes that regulate cell activity can be switched on or off. These include receptors for bone morphogenetic proteins (BMPs) a family of proteins which are potent inducers of bone formation.

BMP receptors have been found on the surface of osteoblasts precursor cells [22] Mbalaviele, G., et al., Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem, 2005. 94 (2): p. 403-18. . Another cell surface receptor called the low-density lipoprotein (LDL)-related protein 5 receptor (LRP5), a Wnt receptor, may also be important for bone formation because loss of LRP5 in animals leads to severe osteoporosis [23] Gong, Y., et al., LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell, 2001. 107 (4): p. 513-23. . BMP receptors and LRP5 may cooperate to stimulate osteoblasts into action, though exactly how this might occur has not been clarified.

Sclerostin, product of the SOST gene and expressed by the osteocytes, binds to LRP5/6 receptor on osteoblasts and inhibits the Wnt signalling, leading to a decrease in bone formation [24] Bonewald, L.F., The amazing osteocyte . J Bone Miner Res, 2011. 26 (2): p. 229-38. [25] Li, X., et al., Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling . J Biol Chem, 2005. 280 (20): p. 19883-7. . Parathyroid hormone (PTH) and mechanical loading decrease the secretion of sclerostin by the oesteocytes [26] Bellido, T., et al., Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis.Endocrinology, 2005. 146 (11): p. 4577-83. [27] Robling, A.G., et al., Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin . J Biol Chem, 2008. 283 (9): p. 5866-75. . An antibody against sclerostin has been developed as a potential drug with potent properties on bone strength. Read more on anabolics  as treatments .  

Figure taken from Ferrari & Roux, 2019  [7] Pocket Reference to Osteoporosis , S. Ferrari, Roux, C., Editor 2019, Springer International Publishing. . 

A cell surface receptor called RANK (for receptor activator of NFκB) prods osteoclasts precursor cells to develop into fully differentiated osteoclasts when RANK is activated by its cognate partner RANK ligand (RANKL) [28] Yasuda, H., et al., Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A, 1998. 95 (7): p. 3597-602. [29] Lacey, D.L., et al., Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation . Cell, 1998. 93 (2): p. 165-76. .

RANKL, in fact, is produced by osteoblasts and is one of perhaps many signalling molecules that facilitate cross-talk between the osteoblasts and osteoclasts and help coordinate bone remodelling [30] Theill, L.E., W.J. Boyle, and J.M. Penninger, RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol, 2002. 20 : p. 795-823. . Osteoprotegerin, another protein released by osteoblasts [31] Suda, T., et al., Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families . Endocr Rev, 1999. 20 (3): p. 345-57. , can also bind to RANKL, acting as a decoy to prevent RANK and RANKL from coming in contact. The balance of RANKL/osteoprotegerin may be crucial in osteoporosis. In fact, animal studies showed that increased production of osteoprotegerin leads to an increase in bone mass, while loss of the protein leads to osteoporosis and increased fractures [32] Bucay, N., et al., osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification . Genes Dev, 1998. 12 (9): p. 1260-8. . Inhibitors of RANKL have also shown promise as potential treatment for osteoporosis in humans.  

A second, complementary cell signalling system that helps drive formation and activation of osteoclasts was also uncovered within the last few years. In the absence of DNAX-activating protein 12 (DAP12) and Fc Receptor common γ chain (FcRγ), two cell surface receptors, mice develop severe osteoporosis – the exact opposite of osteoporosis – characterized by a dramatic increase in bone density [33] Mocsai, A., et al., The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase . Proc Natl Acad Sci U S A, 2004. 101 (16): p. 6158-63. [34] Koga, T., et al., Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis . Nature, 2004. 428 (6984): p. 758-63. . These two cell surface receptors interact with a group of proteins in the cell called ITAM (immunoreceptor tyrosine-based activation motif) adaptor proteins to cause an increase in intracellular calcium.

Studies suggest that the RANK/RANKL and the ITAM-mediated pathways cooperated to induce full osteoclasts activity. These two pathways may converge to activate a protein called the nuclear factor of activated T cells (NFAT) c1. NFATc1 serves as a master switch for bone resorption because it turns on the genes that osteoclasts precursor cells need to become fully active osteoclasts [35] Takayanagi, H., Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med (Berl), 2005. 83 (3): p. 170-9. .

The role of genetics and environmental factors

Subtle differences in the genetic code might explain why one person’s osteoblasts or osteoclasts are more active or responsive to their environment, and it might also lead to the discovery of unknown regulatory mechanisms. Environmental factors can also have an enormous impact on bone physiology. See risk factors for more information.

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Osteoporosis: An Update on Screening, Diagnosis, Evaluation, and Treatment

Shahbaaz a. sabri.

1 University of Colorado School of Medicine, Department of Orthopedic Surgery, Denver, CO

Joseph C. Chavarria

Cheryl ackert-bicknell, christine swanson.

2 University of Colorado School of Medicine, Department of Endocrinology, Metabolism and Diabetes Denver, CO

Evalina Burger

Osteoporosis screening, diagnosis, and treatment have gained much attention in the health care community over the past two decades. During this time, creation of multispecialty awareness programs [e.g., “Own the Bone,” American Orthopedic Association (AOA), “Capture the Fracture,” International Osteoporosis Foundation (IOF), etc.], and improvements in diagnostic protocols have been evident. Significant advances in technology have elucidated elements of genetic predisposition for decreased bone mineral density in the aging population. Additionally, several novel drug therapies have entered the market and provide more options for primary care and osteoporosis specialists to medically manage patients at risk for fragility fractures. Despite this, adherence to osteoporosis screening and treatment protocols has been surprisingly low by health care practitioners, including orthopedic surgeons. Continued awareness and education of this skeletal disorder is crucial to effectively care for our aging population.

Introduction:

Over a person’s lifespan, bone is acquired during growth, reaches peak bone mineral density (BMD) in early adulthood and is lost with advancing age. Osteoporosis is defined as a low BMD with deterioration in the microarchitectural structure of bone tissue resulting in skeletal fragility and increased risk of fracture [ 1 , 2 ]. Previous studies estimated a 10.3% prevalence of osteoporosis in the United States amongst individuals 50 years of age or greater [ 3 ]. In 2017, Wright et al demonstrated approximately 16.9% of men and 29.9% of women 50 years or older meet the updated diagnostic criteria for osteoporosis as defined by the National Bone Health Alliance (NBHA). This prevalence increases to 46.3% in men and 77.1% in women 80 years or older [ 4 ].

The most obvious clinical sign of osteoporosis is a fragility fracture. When considering fracture risk, Strom et al estimated a lifetime risk of developing a major osteoporotic fracture (spine, hip, forearm, humerus) at 46.4% for women and 22.4% for men [ 5 ]. In 2000, the worldwide incidence of fragility fractures was estimated to be 9.0 million and projections show a total of 3 million fragility fractures in the United States alone by 2025 [ 6 , 7 ]. Osteoporotic fractures have been shown to account for loss of more Disability Adjusted Life Years (DALYs), than most common cancers and a fragility hip fracture has almost a 30% 1-year mortality rate [ 6 , 8 ]. This underscores the importance of recognizing and treating osteoporosis as well as advancing our understanding of the disease to develop newer therapeutics with fewer side effects.

Osteoporosis and Genetics:

While fracture is the clinical event of most importance in osteoporosis, this phenotype can be challenging to study genetically [ 9 ]. Parental osteoporotic fracture is predictive of future risk of fracture in their children, highlighting the existence of a genetic contribution to this disease [ 16 , 17 ]. There are a large number of rare monogenic diseases that can impact bone mass and strength, but these disease alleles contribute very little to the variation observed in BMD in the population as a whole [ 10 , 11 ]. Rather, BMD is a complex trait with multiple alleles dictating the genetic proportion of peak BMD in any one person [ 12 ]. The proportion of heritable genetic influence on peak BMD has been estimated to be as high as 85% and equally high heritabilities have been noted for bone architectural phenotypes that are predictive of fracture [ 13 – 16 ].

Historically, linkage analysis and candidate gene testing were used to find associations between regions of the genome and a phenotype of interest, but these have not been successful in finding the actual genes associated with BMD [ 17 , 18 ]. There are many types of genetic changes that can cause differences in phenotype and/or lead to disease. While mutations can involve multiple base pairs, such as is seen with genomic duplications and deletions, mutations may be as a small as a single base pair (SNP). Genome wide association studies (GWAS) are now much more frequently used for genetic mapping. In short, a GWAS is an approach by which the whole genome is examined for associations between genotype and phenotype (reviewed in [ 18 ]). A population ranging in size from a few hundred to several thousand persons is phenotyped for a trait of interest. Then arrays are used to find associations between phenotypes of interest and SNP variants. Across the human population, approximately 10 million SNPs have been found and on average there is a SNP every 300 base pairs [ 19 ]. Genetic variants may alter the amino acid composition and potentially the function of a protein product of a gene [ 9 ]. However, in complexly inherited diseases such as osteoporosis, the causative variant is often located outside of the protein coding region of the gene and may affect the expression of a single gene or multiple genes in a region [ 20 ].

What has GWAS taught us about osteoporosis?

The first GWAS for BMD was conducted on data from ~1000 people from the Framingham Osteoporosis Study and established the principle that BMD could be investigated using GWAS [ 21 ]. In 2009, Rivadeneira identified twenty GWAS loci for BMD that met the accepted significance cut off [ 22 ]. In the intervening decade, a large number of GWAS studies have been conducted in adults, yielding loci associated with BMD of the total hip, forearm, spine and more recently for whole body BMD sans the head (reviewed in [ 23 ]). A recent meta-analysis of GWAS for whole body BMD showed that when the data was stratified by age, only 2 of the 80 identified loci were impacted by age. This means that the majority of genetic loci exert their effects by impacting peak BMD and that the consequences of these loci on peak BMD persist over the life of the individual. In essence, osteoporosis is a young person’s disease wherein there is a failure to acquire adequate peak BMD, predisposing a person for fragility fracture in later life.

Osteoporosis is an exceedingly complex common disease. Historically, GWAS was conducted under the common variant hypothesis which roughly stated that common disease was caused by common variants [ 18 ]. The newest studies include rare variants in the analysis and show that the effect size of rare variants is often larger than that of common variants, but this explains only ~20% of the population variance in BMD [ 12 ]. Likely, some of this can be ascribed to gene by environment (G*E) and gene by gene (G*G) interactions that could not be accounted for in study design [ 18 ] An interpretation of these results is that “osteoporosis” is actually a collection of syndromes, but it is unknown at this time if parsing out the “kind” of osteoporosis a person has would be of clinical value.

There has been much interest in using these results to calculate risk scores to identify patients at high risk for developing disease [ 24 ]. In principle, these risk scores are not that different than risk assessment tools already available, such as the commonly used fracture risk assessment calculator, FRAX [ 25 ]. A polygenic risk score totals how many disease-associated variants a person has, weighs each variant based on how much of an effect that variant has on the phenotype and yields a mathematical calculation of the risk of developing a disease based on their genotypes [ 24 ]. There have been mixed results to date in the creation of polygenic risk scores for osteoporosis, but this is a quickly evolving and promising area of research [ 26 ]. A hope for this technology is these scores can be used to determine who might benefit most from costly medications that are not without serious side effects, such as romosozumab, which is effective in preventing fracture, but is associated with increased risk for stroke and heart attacks [ 26 ].

Diagnosis of Osteoporosis:

The diagnosis of osteoporosis is made when patients meet any of the following criteria [ 27 , 28 ]:

• Fragility fracture
• T-score ≤−2.5 at the lumbar spine, femoral neck, total hip or distal 1/3 radius on DXA exam
• T-score between −1.0 and −2.5 with elevated fracture risk as determined by country-specific thresholds using the online Fracture Risk Assessment Tool (FRAX) [ 29 ]. In the United States, the cutoffs for 10-year fracture risk estimates are ≥20% risk of major osteoporotic fracture and ≥3% risk of hip fracture.

The lowest T-score on an individual’s DXA exam is used for diagnosis. For example, a postmenopausal 65 year old woman with a T-score of −2.6 at the lumbar spine and −2.0 at the left femoral neck and left total hip meets criteria for osteoporosis and should not be classified as having osteoporosis at the spine and osteopenia at the hip. The National Osteoporosis Foundation recommends screening DXA to assess BMD at the lumbar spine and one or both hips (± distal radius under certain clinical circumstances such as primary hyperparathyroidism) in the following groups [ 27 ]:

• Women ≥65 years old
• Men ≥70 years old
• Postmenopausal women and men ≥50 years old with risk factors for osteoporosis (e.g., premature menopause, rheumatoid arthritis, use of bone harming medications) and those with a history of adult fracture

Clinical Evaluation of Osteoporosis and Secondary Causes of Osteoporosis

Primary osteoporosis is osteoporosis due to aging and/or post-menopausal status. An individual suspected of having osteoporosis, either due to fragility fracture and/or low BMD by DXA, should have an evaluation to rule out secondary causes ( Table 1 ) [ 30 – 34 ]. A DXA machine cannot tell the difference between low BMD due to osteoporosis or low BMD due to osteomalacia. Therefore, the clinician should perform an appropriate evaluation and associated laboratory studies. Secondary causes are found in approximately 30% of post-menopausal women and 50-80% of men [ 32 , 33 ], often in those with very low Z-scores[ 30 ]. Table 1 provides a list of common causes of secondary osteoporosis.

Secondary Causes of Osteoporosis [ 30 – 35 ]

Evaluation for secondary causes of osteoporosis consists of a thorough History and Physical Exam (H&P) and preliminary laboratory evaluation. The H&P should be targeted at fracture history (particularly number, site, trauma vs. atraumatic, age of onset) and predisposing factors for low BMD including genetic (family history) or environmental exposures (tobacco use, excess alcohol/caffeine intake, exposure to steroids or other bone harming medications, malabsorption, or inadequate intake etc). For women, age at menarche, and menstrual, obstetric, and menopausal histories, including use of hormones, should be sought. It may also be important to determine if low BMD is due to low peak BMD or ongoing bone loss. For most Orthopedic Surgeons, this goes beyond the typical scope of practice and therefore, we recommend referral to either a patient’s primary care provider or an endocrinologist. With that being said, these physicians often have a significant wait time for evaluation and all physicians should be able to initiate the initial work up for osteoporosis.

Table 2 contains a suggested laboratory evaluation to rule out secondary causes of osteoporosis in otherwise healthy individuals. The suggested panel should identify >90% of secondary causes of osteoporosis, if present [ 32 , 36 ]. In particular, osteomalacia, due to inadequate calcium (often due to vitamin D deficiency) or phosphorous, must be ruled out or treated prior to initiating pharmacotherapy to avoid increased risk of side effects (e.g., hypocalcemia with anti-resorptive medications). Additional lab evaluation (SPEP/UPEP, celiac panel, magnesium, serum tryptase, 1mg dexamethasone suppression test, 1,25-dihydroxyvitamin D, bone turnover markers) should be performed as guided by H&P findings and co-morbidities. If height loss is reported or observed, imaging of the thoracic and lumbar spine should be performed to rule out vertebral compression fractures ( Table 3 ). Recent chest x-rays and/or abdominal imaging can be used to evaluate the spine without additional cost or radiation exposure.

Suggested Lab Evaluation for Secondary Causes of Osteoporosis [ 30 – 32 , 36 ]

NOF Guidelines Criteria for Performing Dedicated Vertebral Imaging [ 31 ]

Updates in Osteoporosis Treatment

Once osteoporosis has been confirmed and any underlying abnormalities have been corrected (e.g., Vitamin D Deficiency, primary hyperparathyroidism), treatment should be considered in those individuals meeting appropriate criteria [ 30 , 31 , 37 , 38 ] ( Table 4 ). Diagnosis and treatment of osteoporosis has fallen over recent decades in part due to lack of recognition that fragility fractures are diagnostic of osteoporosis and fear of medication side effects [ 39 ]. Orthopedists are often the first providers involved in patient care when a fracture occurs and, therefore, are uniquely positioned to inform the patient who experienced a fragility fracture that they have osteoporosis and should have appropriate osteoporosis evaluation and treatment. Fracture Liaison Services (FLS, see below) can assist orthopedists with the evaluation and treatment of osteoporosis when patients present with fracture. Importantly, osteoporosis therapy consists of pharmacologic and NON-pharmacologic treatments.

Individuals in Whom Pharmacological Therapy Should Be Considered [ 30 , 31 , 37 , 38 ]

Non-pharmacological therapy includes adequate calcium/vitamin D/protein intake, smoking cessation, fall prevention, avoiding bone-harming medications (if possible), maintaining a healthy weight, remaining active with weight-bearing exercise and avoiding excess alcohol and caffeine intake. The Institute of Medicine[ 40 ] and National Osteoporosis Foundation[ 31 ] recommend individuals over the age of 50 years target 1000-1200mg of calcium per day, including and preferably via dietary intake [ 37 , 38 ]. If a supplement is needed to make up the difference in those unable to get the recommended amount exclusively via diet, calcium carbonate (40% elemental calcium, must be taken with food) or calcium citrate (21% elemental calcium, more expensive, can be taken with or without food, better absorbed in achlorhydria such as PPI use or gastric bypass) may be used. The Institute of Medicine[ 40 ] recommends 400-600 IU/day of Vitamin D for healthy adults 51 years of age or older whereas most osteoporosis guidelines recommend 800-2000IU/day to achieve adequate 25-hydroxyvitamin D levels [ 30 , 31 , 37 , 38 ]. The appropriate vitamin D level is a matter of debate [ 40 , 41 ]. Our practice is in line with the Endocrine Society Guidelines targeting a 25-hydroxyvitamin D level of 30 ng/mL [ 30 , 41 ]. Vitamin D3 (aka cholecalciferol) is preferred to Vitamin D2 due to its longer half-life [ 42 ]. Calcium and vitamin D are “threshold” vitamins, meaning that adequate amounts are important for mineralization, maintaining BMD, and avoiding excess BMD loss but more (and particularly excessive amounts) are not necessarily better.

Osteoporosis pharmacotherapy ( Table 5 ) is classically divided into two categories, anti-resorptive or anabolic. Societal guidelines are available that provide suggested treatment algorithms to help medical providers select the appropriate pharmacotherapy for their patients [ 28 , 37 , 38 ]. Anti-resorptive therapies (bisphosphonates, denosumab, raloxifene) target and block osteoclast activity to decrease bone resorption and BMD loss. All anti-resorptive therapies can cause hypocalcemia and are associated with osteonecrosis of the jaw (ONJ) and atypical femur fracture (AFF) which occur in less than 1% of patients[ 43 – 45 ]. Anabolic therapies (e.g., teriparatide, abaloparatide) transiently stimulate the PTH receptor to stimulate osteoblasts and bone formation. The most recently FDA-approved osteoporosis medication, romosozumab, is a monoclonal antibody to sclerostin and therefore has both anti-resorptive and anabolic features. By inhibiting sclerostin (an inhibitor of bone formation), romosozumab stimulates bone formation and suppresses bone resorption [ 46 ]. In the FRAME study [ 47 ], romosozumab for 12 months followed by 12 months of denosumab significantly decreased the risk of vertebral in post-menopausal women with osteoporosis compared to placebo for 12 months followed by 12 months of denosumab (RR 0.25, p < 0.001). Although romosozumab resulted in significantly greater increases in BMD at the lumbar spine, total hip, and femoral neck, non-vertebral and hip fractures were not statistically significantly different between the romosozumab and placebo groups. Similar to other anti-resorptive medications, osteonecrosis of the jaw and atypical femur fractures have been reportedly rarely with romosozoumab [ 47 ]. Uniquely, romosozumab carries a black box warning for potentially increased risk of myocardial infarction, stroke, and cardiovascular death and should not be initiated in those who have had a cardiovascular event within the previous 12 months. Romosozumab is a subcutaneous injection administered in a healthcare facility monthly and is only approved for 12 months of use.

Pharmacological Treatment Options for Osteoporosis

Assessment of Osteoporosis Management:

Despite the increasing prevalence of osteoporosis and expected increase in fragility fracture rate, there appears to be an overall poor adherence to osteoporosis screening and treatment protocols. Studies have found that <25% of patients for whom osteoporosis screening is recommended receive such screening [ 61 ]. A 2019 study demonstrated that in patients 50 year or older who presented to the emergency department with a vertebral fragility fracture, only 27% were receiving medical therapy for osteoporosis prior to their fracture [ 7 ]. While our knowledge of screening guidelines and adherence to their recommendations certainly lacks, as does our post-fragility fracture care of bone health. Studies demonstrate an almost 200% increased risk of subsequent fragility fracture and an almost 300% increased risk of hip fracture following a vertebral fragility fracture [ 62 ]. In 2016, Oertel et al evaluated osteoporosis management in 1375 geriatric patients following fragility fractures and found only 21% of patients were previously tested for bone mineral density or received osteoporosis treatment [ 63 ]. Similarly, another study found that one year after fragility fracture, over 90% of patients failed to receive a bone density scan or start empiric treatment for osteoporosis [ 7 ]. Ultimately, 38% of patients in this study went on to develop a second osteoporotic fracture within 2 years of their initial fragility fracture [ 7 ]. These results highlight the fact that we are slow to diagnose and treat osteoporosis before fragility fractures occur. Even more concerning, they demonstrate a generalized lack of understanding about the need for testing and treatment following fragility fractures in order to prevent future fractures.

Beyond the lack of understanding about the need for testing and treatment for osteoporosis, there are also significant patient factors to consider, especially non-compliance. While there are a variety of reasons for poor patient compliance, it has previously been shown that patient adherence to treatment correlates with decreased fragility fracture risk as well as improvement in BMD [ 64 ]. Therefore, it is incredibly important to discuss areas of patient concern including their understanding of the diagnosis and treatment plan, as well as the potential consequences of untreated osteoporosis as well as the side effects of medications. While clinicians believe >67% of their patients are taking their prescribed osteoporosis medications, only 40% of patients are picking those medications and it is likely that even fewer are actually taking these medications as prescribed [ 65 ]. From a patient stand-point, the major reasons for non-compliance include side effect profile of medications, lack of education/awareness of benefits of treatment, as well as dosing/administration inconveniences [ 65 ]. It is our recommendation that practitioners treating osteoporosis have an in-depth discussion with their patient regarding the side effect profile of the medications they prescribe. They should also stress the significant morbidity/mortality associated with untreated osteoporosis and the benefits of treatment.

Areas of Improvement:

Initially implemented in the UK, a Fracture Liaison Service (FLS) is a coordinator based, post fracture model of care designed to close the gap between sentinel fragility fracture and secondary fracture [ 66 ]. The aim is to create a structured pathway to improve identification, evaluation, and implementation of appropriate treatment in patients at risk of a secondary fragility fracture. A successful FLS program generally consists of a core of three individuals. These include a physician leader, FLS coordinator, and nurse navigator. Outside the core, significant multispecialty assistance is necessary and includes orthopedic surgery, rheumatology, endocrinology, primary care, and nursing support [ 67 ]. The International Osteoporosis Foundation (IOF) launched their “Capture the Fracture” program in 2012 and provided guidance on development of FLS programs globally [ 68 ]. When comparing institutions with FLS programs in place versus non-FLS institutions, an approximate 30% reduction in any re-fracture and 40% reduction in major re-fractures have been reported [ 69 ]. Gupta et al described their institution’s unique FLS program supplemented with EMR based alerts. These alerts helped identify at-risk patients who were admitted to the hospital or evaluated in the emergency department. After implementation for 12 months, the authors reported their ability to identify “captured missed opportunities” in 73.1% of previously undiagnosed and 77.1% of previously untreated osteoporosis patients [ 70 ]. Although success of FLS may vary, key factors that influence effectiveness include a multidisciplinary involvement, dedicated case managers, regular assessment and follow up, multifaceted interventions, and patient education [ 71 ]. The authors of this paper recommend that an FLS be developed at each institution in order to improve diagnosis and treatment of individuals suffering from osteoporosis.

In 2004, The US Surgeon General report warned that in 2020, the prevalence of osteoporosis and low bone mass is expected to increase to 1 in 2 Americans over age 50. We have made significant progress in understanding the genetic etiology of osteoporosis and development of treatments [ 72 ]. As our understanding of this diseased has improved, a greater number of pharmacotherapy options have become available for treatment.

While we continue to make great strides in the understanding of the disease and development of treatment modalities, there is continued need for improvement in screening and implementation of treatment. Many age-appropriate patients do not receive screening or counselling on osteoporosis. Furthermore, patients with known fragility fractures do not consistently receive the osteoporosis care and treatment they most certainly need. With more than 53 million people in the US alone affected by this disease, a thorough understanding of the basis, screening, diagnosis and treatment of osteoporosis is vital for all practitioners.

Acknowledgments

Dr. Swanson would like to acknowledge her funding (K23 AR070275, R03 AR074509)

References:

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Osteoporosis: molecular pathology, diagnostics, and therapeutics.

1. Introduction

2. cellular and molecular mechanisms, 2.1. structural and cellular components of bone, 2.2. bone homeostasis, 2.3. molecular and local regulation, 3. osteoporosis pathophysiology, 3.1. osteoimmunological model, 3.2. gut microbiome model, 3.3. cellular senescence model, 3.4. genetic component of osteoporosis, 4. diagnosing osteoporosis, novel diagnostic approaches, 5. treatment options, 5.1. non-pharmacological treatment options, 5.2. pharmacological treatment options, 5.2.1. calcium and vitamin d supplementation, 5.2.2. antiresorptive agents, bisphosphonates, 5.2.3. hormonal agents, estrogen and selective estrogen receptor modulators (serms), pth analogues, 5.2.4. novel therapies, romosozumab, 5.3. orthopedic management of fragility fractures.

• Vertebral Fractures:
• Hip Fractures:
• Proximal Humerus Fractures:
• Distal Radius Fractures:
• Atypical Femur Fractures:

6. Conclusions and Future Prospects

Conflicts of interest.

• Rosen, C.J. The Epidemiology and Pathogenesis of Osteoporosis. In Endotext ; Feingold, K.R., Anawalt, B., Boyce, A., Blackman, M.R., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., Dungan, K., Hofland, J., et al., Eds.; MDText.com, Inc.: South Dartmouth, MA, USA, 2000. Available online: http://www.ncbi.nlm.nih.gov/books/NBK279134/ (accessed on 9 January 2023).
• Shen, Y.; Huang, X.; Wu, J.; Lin, X.; Zhou, X.; Zhu, Z.; Pan, X.; Xu, J.; Qiao, J.; Zhang, T.; et al. The Global Burden of Osteoporosis, Low Bone Mass, and Its Related Fracture in 204 Countries and Territories, 1990–2019. Front. Endocrinol. 2022 , 13 , 882241. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rashki Kemmak, A.; Rezapour, A.; Jahangiri, R.; Nikjoo, S.; Farabi, H.; Soleimanpour, S. Economic burden of osteoporosis in the world: A systematic review. Med. J. Islam. Repub. Iran 2020 , 34 , 154. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Li, H.; Xiao, Z.; Quarles, L.D.; Li, W. Osteoporosis: Mechanism, Molecular Target and Current Status on Drug Development. Curr. Med. Chem. 2021 , 28 , 1489–1507. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Gao, Y.; Patil, S.; Jia, J. The Development of Molecular Biology of Osteoporosis. Int. J. Mol. Sci. 2021 , 22 , 8182. [ Google Scholar ] [ CrossRef ]
• Aibar-Almazán, A.; Voltes-Martínez, A.; Castellote-Caballero, Y.; Afanador-Restrepo, D.F.; del Carcelén-Fraile, M.C.; López-Ruiz, E. Current Status of the Diagnosis and Management of Osteoporosis. Int. J. Mol. Sci. 2022 , 23 , 9465. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Barnsley, J.; Buckland, G.; Chan, P.E.; Ong, A.; Ramos, A.S.; Baxter, M.; Laskou, F.; Dennison, E.M.; Cooper, C.; Patel, H.P. Pathophysiology and treatment of osteoporosis: Challenges for clinical practice in older people. Aging Clin. Exp. Res. 2021 , 33 , 759–773. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Robey, P.G. Vertebrate Mineralized Matrix Proteins: Structure and Function. Connect. Tissue Res. 1996 , 35 , 131–136. [ Google Scholar ] [ CrossRef ]
• Iconaru, L.; Moreau, M.; Baleanu, F.; Kinnard, V.; Charles, A.; Mugisha, A.; Surquin, M.; Benoit, F.; Karmali, R.; Paesmans, M.; et al. Risk factors for imminent fractures: A substudy of the FRISBEE cohort. Osteoporos. Int. 2021 , 32 , 1093–1101. [ Google Scholar ] [ CrossRef ]
• Burr, D.B.; Akkus, O. Chapter 1—Bone Morphology and Organization. In Basic and Applied Bone Biology ; Burr, D.B., Allen, M.R., Eds.; Academic Press: Cambridge, MA, USA, 2014; pp. 3–25. [ Google Scholar ] [ CrossRef ]
• Siddiqui, J.A.; Partridge, N.C. Physiological Bone Remodeling: Systemic Regulation and Growth Factor Involvement. Physiology 2016 , 31 , 233–245. [ Google Scholar ] [ CrossRef ]
• Rowe, P.; Koller, A.; Sharma, S. Physiology, Bone Remodeling ; StatPearls Publishing: St. Petersburg, FL, USA, 2022. Available online: http://www.ncbi.nlm.nih.gov/books/NBK499863/ (accessed on 15 January 2023).
• Yang, T.L.; Shen, H.; Liu, A.; Dong, S.-S.; Zhang, L.; Deng, F.-Y.; Zhao, Q.; Deng, H.-W. A road map for understanding molecular and genetic determinants of osteoporosis. Nat. Rev. Endocrinol. 2020 , 16 , 91–103. [ Google Scholar ] [ CrossRef ]
• Sözen, T.; Özışık, L.; Başaran, N.Ç. An overview and management of osteoporosis. Eur. J. Rheumatol. 2017 , 4 , 46–56. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Föger-Samwald, U.; Dovjak, P.; Azizi-Semrad, U.; Kerschan-Schindl, K.; Pietschmann, P. Osteoporosis: Pathophysiology and therapeutic options. EXCLI J. 2020 , 19 , 1017–1037. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Clarke, B.L.; Khosla, S. Physiology of bone loss. Radiol. Clin. N. Am. 2010 , 48 , 483–495. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Johnston, E.; Buckley, M. Age-Related Changes in Post-Translational Modifications of Proteins from Whole Male and Female Skeletal Elements. Molecules 2023 , 28 , 4899. [ Google Scholar ] [ CrossRef ]
• Horton, J.E.; Raisz, L.G.; Simmons, H.A.; Oppenheim, J.J.; Mergenhagen, S.E. Bone resorbing activity in supernatant fluid from cultured human peripheral blood leukocytes. Science 1972 , 177 , 793–795. [ Google Scholar ] [ CrossRef ]
• Sato, K.; Suematsu, A.; Okamoto, K.; Yamaguchi, A.; Morishita, Y.; Kadono, Y.; Tanaka, S.; Kodama, T.; Akira, S.; Iwakura, Y.; et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 2006 , 203 , 2673–2682. [ Google Scholar ] [ CrossRef ]
• Zhao, R.; Wang, X.; Feng, F. Upregulated Cellular Expression of IL-17 by CD4+ T-Cells in Osteoporotic Postmenopausal Women. Ann. Nutr. Metab. 2016 , 68 , 113–118. [ Google Scholar ] [ CrossRef ]
• Cline-Smith, A.; Axelbaum, A.; Shashkova, E.; Chakraborty, M.; Sanford, J.; Panesar, P.; Peterson, M.; Cox, L.; Baldan, A.; Veis, D.; et al. Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2020 , 35 , 1174–1187. [ Google Scholar ] [ CrossRef ]
• Zaiss, M.M.; Sarter, K.; Hess, A.; Engelke, K.; Böhm, C.; Nimmerjahn, F.; Voll, R.; Schett, G.; David, J.-P. Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. Arthritis Rheum. 2010 , 62 , 2328–2338. [ Google Scholar ] [ CrossRef ]
• Walsh, M.C.; Choi, Y. Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond. Front. Immunol. 2014 , 5 , 511. [ Google Scholar ] [ CrossRef ]
• Panach, L.; Serna, E.; Tarín, J.J.; Cano, A.; García-Pérez, M.Á. A translational approach from an animal model identifies CD80 as a candidate gene for the study of bone phenotypes in postmenopausal women. Osteoporos. Int. J. Establ. Result. Coop. Eur. Found. Osteoporos. Natl. Osteoporos. Found. USA 2017 , 28 , 2445–2455. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Behera, J.; Ison, J.; Tyagi, S.C.; Tyagi, N. The role of gut microbiota in bone homeostasis. Bone 2020 , 135 , 115317. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ding, K.; Hua, F.; Ding, W. Gut Microbiome and Osteoporosis. Aging Dis. 2020 , 11 , 438–447. [ Google Scholar ] [ CrossRef ]
• Pacifici, R. Bone Remodeling and the Microbiome. Cold Spring Harb. Perspect. Med. 2018 , 8 , a031203. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rodrigues, F.C.; Castro, A.S.B.; Rodrigues, V.C.; Fernandes, S.A.; Fontes, E.A.F.; de Oliveira, T.T.; Martino, H.S.D.; Ferreira, C.L.d.L.F. Yacon flour and Bifidobacterium longum modulate bone health in rats. J. Med. Food. 2012 , 15 , 664–670. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Whisner, C.M.; Martin, B.R.; Nakatsu, C.H.; McCabe, G.P.; McCabe, L.D.; Peacock, M.; Weaver, C.M. Soluble maize fibre affects short-term calcium absorption in adolescent boys and girls: A randomised controlled trial using dual stable isotopic tracers. Br. J. Nutr. 2014 , 112 , 446–456. [ Google Scholar ] [ CrossRef ]
• Whisner, C.M.; Martin, B.R.; Nakatsu, C.H.; Story, J.A.; MacDonald-Clarke, C.J.; McCabe, L.D.; McCabe, G.P.; Weaver, C.M. Soluble Corn Fiber Increases Calcium Absorption Associated with Shifts in the Gut Microbiome: A Randomized Dose-Response Trial in Free-Living Pubertal Females. J. Nutr. 2016 , 146 , 1298–1306. [ Google Scholar ] [ CrossRef ]
• Zaiss, M.M.; Jones, R.M.; Schett, G.; Pacifici, R. The gut-bone axis: How bacterial metabolites bridge the distance. J. Clin. Investig. 2019 , 129 , 3018–3028. [ Google Scholar ] [ CrossRef ]
• Lucas, S.; Omata, Y.; Hofmann, J.; Böttcher, M.; Iljazovic, A.; Sarter, K.; Albrecht, O.; Schulz, O.; Krishnacoumar, B.; Krönke, G.; et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat. Commun. 2018 , 9 , 55. [ Google Scholar ] [ CrossRef ]
• Li, J.Y.; Yu, M.; Pal, S.; Tyagi, A.M.; Dar, H.; Adams, J.; Weitzmann, M.N.; Jones, R.M.; Pacifici, R. Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota. J. Clin. Investig. 2020 , 130 , 1767–1781. [ Google Scholar ] [ CrossRef ]
• Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 1965 , 37 , 614–636. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tchkonia, T.; Zhu, Y.; van Deursen, J.; Campisi, J.; Kirkland, J.L. Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J. Clin. Investig. 2013 , 123 , 966–972. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Khosla, S.; Farr, J.N.; Kirkland, J.L. Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. J. Clin. Endocrinol. Metab. 2018 , 103 , 1282–1290. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Farr, J.N.; Fraser, D.G.; Wang, H.; Jaehn, K.; Ogrodnik, M.B.; Weivoda, M.M.; Drake, M.T.; Tchkonia, T.; LeBrasseur, N.K.; Kirkland, J.L.; et al. Identification of Senescent Cells in the Bone Microenvironment. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2016 , 31 , 1920–1929. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Farr, J.N.; Xu, M.; Weivoda, M.M.; Monroe, D.G.; Fraser, D.G.; Onken, J.L.; Negley, B.A.; Sfeir, J.G.; Ogrodnik, M.B.; Hachfeld, C.M.; et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 2017 , 23 , 1072–1079. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mäkitie, R.E.; Costantini, A.; Kämpe, A.; Alm, J.J.; Mäkitie, O. New Insights into Monogenic Causes of Osteoporosis. Front. Endocrinol. 2019 , 10 , 70. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Zhang, X.; Deng, H.W.; Shen, H.; Ehrlich, M. Prioritization of Osteoporosis-Associated Genome-wide Association Study (GWAS) Single-Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics. JBMR Plus 2021 , 5 , e10481. [ Google Scholar ] [ CrossRef ]
• Baron, R.; Kneissel, M. WNT signaling in bone homeostasis and disease: From human mutations to treatments. Nat. Med. 2013 , 19 , 179–192. [ Google Scholar ] [ CrossRef ]
• Zhong, W.; Pathak, J.L.; Liang, Y.; Zhytnik, L.; Pals, G.; Eekhoff, E.M.; Bravenboer, N.; Micha, D. The intricate mechanism of PLS3 in bone homeostasis and disease. Front. Endocrinol. 2023 , 14 , 1168306. [ Google Scholar ] [ CrossRef ]
• Hu, J.; Zhou, B.; Lin, X.; Zhang, Q.; Guan, F.; Sun, L.; Liu, J.; Wang, O.; Jiang, Y.; Xia, W.-B.; et al. Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation. eLife 2023 , 12 , e80365. [ Google Scholar ] [ CrossRef ]
• Doddato, G.; Fabbiani, A.; Fallerini, C.; Bruttini, M.; Hadjistilianou, T.; Landi, M.; Coradeschi, C.; Grosso, S.; Tomasini, B.; Mencarelli, M.A.; et al. Spondyloocular Syndrome: A Novel XYLT2 Variant with Description of the Neonatal Phenotype. Front. Genet. 2021 , 12 , 761264. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Basta, M.D.; Petruk, S.; Summer, R.; Rosenbloom, J.; Wermuth, P.J.; Macarak, E.; Levin, A.V.; Mazo, A.; Walker, J.L. Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis. iScience 2023 , 26 , 106570. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Blake, G.M.; Fogelman, I. The role of DXA bone density scans in the diagnosis and treatment of osteoporosis. Postgrad. Med. J. 2007 , 83 , 509–517. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Heilmeier, U.; Youm, J.; Torabi, S.; Link, T.M. Osteoporosis Imaging in the Geriatric Patient. Curr. Radiol. Rep. 2016 , 4 , 18. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bhattacharya, P.; Altai, Z.; Qasim, M.; Viceconti, M. A multiscale model to predict current absolute risk of femoral fracture in a postmenopausal population. Biomech. Model. Mechanobiol. 2019 , 18 , 301–318. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Barbosa, C.C.L.; da Costa, J.C.; Romanzini, C.L.P.; Batista, M.B.; Blasquez-Shigaki, G.; Fernandes, R.A.; Martinho, D.V.; Oliveira, T.; Ribeiro, L.P.; Coelho-E-Silva, M.J.; et al. Interrelationship between muscle fitness in childhood and bone mineral density in adulthood: Mediation analysis of muscle fitness in adulthood. BMC Public Health 2023 , 23 , 648. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Vasquez, E.; Alam, M.T.; Murillo, R. Race and Ethnic Differences in Physical Activity, Osteopenia, and Osteoporosis: Results from Nhanes. Innov. Aging 2022 , 6 (Suppl. S1), 90. [ Google Scholar ] [ CrossRef ]
• Keen, M.U.; Reddivari, A.K.R. Osteoporosis in Females ; StatPearls Publishing: St. Petersburg, FL, USA, 2022. Available online: http://www.ncbi.nlm.nih.gov/books/NBK559156/ (accessed on 22 January 2023).
• Varacallo, M.; Seaman, T.J.; Jandu, J.S.; Pizzutillo, P. Osteopenia ; StatPearls Publishing: St. Petersburg, FL, USA, 2023. Available online: http://www.ncbi.nlm.nih.gov/books/NBK499878/ (accessed on 26 July 2023).
• Ho-Pham, L.T.; Nguyen, U.D.T.; Pham, H.N.; Nguyen, N.D.; Nguyen, T.V. Reference ranges for bone mineral density and prevalence of osteoporosis in Vietnamese men and women. BMC Musculoskelet. Disord. 2011 , 12 , 182. [ Google Scholar ] [ CrossRef ]
• Wheater, G.; Elshahaly, M.; Tuck, S.P.; Datta, H.K.; van Laar, J.M. The clinical utility of bone marker measurements in osteoporosis. J. Transl. Med. 2013 , 11 , 201. [ Google Scholar ] [ CrossRef ]
• Lowe, D.; Sanvictores, T.; Zubair, M.; John, S. Alkaline Phosphatase ; StatPearls Publishing: St. Petersburg, FL, USA, 2022. Available online: http://www.ncbi.nlm.nih.gov/books/NBK459201/ (accessed on 22 January 2023).
• Greenblatt, M.B.; Tsai, J.N.; Wein, M.N. Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease. Clin. Chem. 2017 , 63 , 464–474. [ Google Scholar ] [ CrossRef ]
• Earp, B.E.; Kallini, J.R.; Collins, J.E.; Benavent, K.A.; Tintle, S.M.; Rozental, T.D. Correlation of Hounsfield Unit Measurements on Computed Tomography of the Shoulder with Dual-Energy X-ray Absorptiometry Scans and Fracture Risk Assessment Tool Scores: A Potential for Opportunistic Screening. J. Orthop. Trauma 2021 , 35 , 384–390. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Shanb, A.A.; Youssef, E.F. The impact of adding weight-bearing exercise versus nonweight bearing programs to the medical treatment of elderly patients with osteoporosis. J. Fam. Community Med. 2014 , 21 , 176–181. [ Google Scholar ] [ CrossRef ]
• de Labra, C.; Guimaraes-Pinheiro, C.; Maseda, A.; Lorenzo, T.; Millán-Calenti, J.C. Effects of physical exercise interventions in frail older adults: A systematic review of randomized controlled trials. BMC Geriatr. 2015 , 15 , 154. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kujala, U.M.; Kaprio, J.; Kannus, P.; Sarna, S.; Koskenvuo, M. Physical activity and osteoporotic hip fracture risk in men. Arch. Intern. Med. 2000 , 160 , 705–708. [ Google Scholar ] [ CrossRef ]
• Rizzoli, R.; Bianchi, M.L.; Garabédian, M.; McKay, H.A.; Moreno, L.A. Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly. Bone 2010 , 46 , 294–305. [ Google Scholar ] [ CrossRef ]
• Kelley, G.A.; Kelley, K.S.; Tran, Z.V. Exercise and lumbar spine bone mineral density in postmenopausal women: A meta-analysis of individual patient data. J. Gerontol. A Biol. Sci. Med. Sci. 2002 , 57 , M599–M604. [ Google Scholar ] [ CrossRef ]
• Howe, T.E.; Shea, B.; Dawson, L.J.; Downie, F.; Murray, A.; Ross, C.; Harbour, R.T.; Caldwell, L.M.; Creed, G. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst. Rev. 2011 , 7 , CD000333. [ Google Scholar ] [ CrossRef ]
• LeBoff, M.S.; Greenspan, S.L.; Insogna, K.L.; Lewiecki, E.M.; Saag, K.G.; Singer, A.J.; Siris, E.S. The clinician’s guide to prevention and treatment of osteoporosis. Osteoporos. Int. 2022 , 33 , 2049–2102. [ Google Scholar ] [ CrossRef ]
• Al-Bashaireh, A.M.; Haddad, L.G.; Weaver, M.; Chengguo, X.; Kelly, D.L.; Yoon, S. The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms. J. Osteoporos. 2018 , 2018 , 1206235. [ Google Scholar ] [ CrossRef ]
• Al-Bashaireh, A.M.; Alqudah, O. Comparison of Bone Turnover Markers between Young Adult Male Smokers and Nonsmokers. Cureus 2020 , 12 , e6782. [ Google Scholar ] [ CrossRef ]
• Cheraghi, Z.; Doosti-Irani, A.; Almasi-Hashiani, A.; Baigi, V.; Mansournia, N.; Etminan, M.; Mansournia, M.A. The effect of alcohol on osteoporosis: A systematic review and meta-analysis. Drug Alcohol. Depend. 2019 , 197 , 197–202. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Li, S.; Zeng, M. The association between dietary inflammation index and bone mineral density: Results from the United States National Health and nutrition examination surveys. Ren. Fail. 2023 , 45 , 2209200. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Lanyan, A.; Marques-Vidal, P.; Gonzalez-Rodriguez, E.; Hans, D.; Lamy, O. Postmenopausal women with osteoporosis consume high amounts of vegetables but insufficient dairy products and calcium to benefit from their virtues: The CoLaus/OsteoLaus cohort. Osteoporos. Int. J. Establ. Result. Coop. Eur. Found. Osteoporos. Natl. Osteoporos. Found. USA 2020 , 31 , 875–886. [ Google Scholar ] [ CrossRef ]
• Ogilvie, A.R.; McGuire, B.D.; Meng, L.; Shapses, S.A. Fracture Risk in Vegetarians and Vegans: The Role of Diet and Metabolic Factors. Curr. Osteoporos. Rep. 2022 , 20 , 442–452. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Denova-Gutiérrez, E.; Méndez-Sánchez, L.; Muñoz-Aguirre, P.; Tucker, K.L.; Clark, P. Dietary Patterns, Bone Mineral Density, and Risk of Fractures: A Systematic Review and Meta-Analysis. Nutrients 2018 , 10 , 1922. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Shetty, S.; Kapoor, N.; Bondu, J.D.; Thomas, N.; Paul, T.V. Bone turnover markers: Emerging tool in the management of osteoporosis. Indian J. Endocrinol. Metab. 2016 , 20 , 846–852. [ Google Scholar ] [ CrossRef ]
• Weaver, C.M.; Alexander, D.D.; Boushey, C.J.; Dawson-Hughes, B.; Lappe, J.M.; LeBoff, M.S.; Liu, S.; Looker, A.C.; Wallace, T.C.; Wang, D.D. Calcium plus vitamin D supplementation and risk of fractures: An updated meta-analysis from the National Osteoporosis Foundation. Osteoporos. Int. J. Establ. Result. Coop. Eur. Found. Osteoporos. Natl. Osteoporos. Found. USA 2016 , 27 , 367–376. [ Google Scholar ] [ CrossRef ]
• Tang, B.M.P.; Eslick, G.D.; Nowson, C.; Smith, C.; Bensoussan, A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: A meta-analysis. Lancet 2007 , 370 , 657–666. [ Google Scholar ] [ CrossRef ]
• Sanderson, J.; Martyn-St James, M.; Stevens, J.; Goka, E.; Wong, R.; Campbell, F.; Selby, P.; Gittoes, N.; Davis, S. Clinical effectiveness of bisphosphonates for the prevention of fragility fractures: A systematic review and network meta-analysis. Bone 2016 , 89 , 52–58. [ Google Scholar ] [ CrossRef ]
• Zullo, A.R.; Zhang, T.; Lee, Y.; McConeghy, K.W.; Daiello, L.A.; Kiel, D.P.; Mor, V.; Berry, S.D. Effect of Bisphosphonates on Fracture Outcomes among Frail Older Adults. J. Am. Geriatr. Soc. 2019 , 67 , 768–776. [ Google Scholar ] [ CrossRef ]
• Saita, Y.; Ishijima, M.; Kaneko, K. Atypical femoral fractures and bisphosphonate use: Current evidence and clinical implications. Ther. Adv. Chronic Dis. 2015 , 6 , 185–193. [ Google Scholar ] [ CrossRef ]
• Cummings, S.R.; San Martin, J.; McClung, M.R.; Siris, E.S.; Eastell, R.; Reid, I.R.; Delmas, P.; Zoog, H.B.; Austin, M.; Wang, A.; et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 2009 , 361 , 756–765. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Khosla, S.; Hofbauer, L.C. Osteoporosis treatment: Recent developments and ongoing challenges. Lancet Diabetes Endocrinol. 2017 , 5 , 898–907. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Guañabens, N.; Moro-Álvarez, M.J.; Casado, E.; Blanch-Rubió, J.; Gómez-Alonso, C.; Díaz-Guerra, G.M.; del Pino-Montes, J.; de Lamadrid, C.V.D.; Peris, P.; Muñoz-Torres, M.; et al. The next step after anti-osteoporotic drug discontinuation: An up-to-date review of sequential treatment. Endocrine 2019 , 64 , 441–455. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Miller, P.D.; Hattersley, G.; Riis, B.J.; Williams, G.C.; Lau, E.; Russo, L.A.; Alexandersen, P.; Zerbini, C.A.F.; Hu, M.-Y.; Harris, A.G.; et al. Effect of Abaloparatide vs. Placebo on New Vertebral Fractures in Postmenopausal Women with Osteoporosis: A Randomized Clinical Trial. JAMA 2016 , 316 , 722–733. [ Google Scholar ] [ CrossRef ]
• Leder, B.Z. Optimizing Sequential and Combined Anabolic and Antiresorptive Osteoporosis Therapy. JBMR Plus 2018 , 2 , 62–68. [ Google Scholar ] [ CrossRef ]
• Cosman, F.; Crittenden, D.B.; Adachi, J.D.; Binkley, N.; Czerwinski, E.; Ferrari, S.; Hofbauer, L.C.; Lau, E.; Lewiecki, E.M.; Miyauchi, A.; et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N. Engl. J. Med. 2016 , 375 , 1532–1543. [ Google Scholar ] [ CrossRef ]
• McClung, M.R. Romosozumab for the treatment of osteoporosis. Osteoporos. Sarcopenia 2018 , 4 , 11–15. [ Google Scholar ] [ CrossRef ]
• Wijenayaka, A.R.; Kogawa, M.; Lim, H.P.; Bonewald, L.F.; Findlay, D.M.; Atkins, G.J. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS ONE 2011 , 6 , e25900. [ Google Scholar ] [ CrossRef ]
• Ominsky, M.S.; Niu, Q.T.; Li, C.; Li, X.; Ke, H.Z. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2014 , 29 , 1424–1430. [ Google Scholar ] [ CrossRef ]
• Ferrari, S. Future directions for new medical entities in osteoporosis. Best. Pract. Res. Clin. Endocrinol. Metab. 2014 , 28 , 859–870. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Cosman, F.; Crittenden, D.B.; Ferrari, S.; Khan, A.; Lane, N.E.; Lippuner, K.; Matsumoto, T.; Milmont, C.E.; Libanati, C.; Grauer, A. FRAME Study: The Foundation Effect of Building Bone with 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2018 , 33 , 1219–1226. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Saag, K.G.; Petersen, J.; Brandi, M.L.; Karaplis, A.C.; Lorentzon, M.; Thomas, T.; Maddox, J.; Fan, M.; Meisner, P.D.; Grauer, A. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N. Engl. J. Med. 2017 , 377 , 1417–1427. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Miller, S.A.; St Onge, E.L.; Whalen, K.L. Romosozumab: A Novel Agent in the Treatment for Postmenopausal Osteoporosis. J. Pharm. Technol. JPT Off. Publ. Assoc. Pharm. Tech. 2021 , 37 , 45–52. [ Google Scholar ] [ CrossRef ]
• Chinese Orthopaedic Association. Diagnosis and treatment of osteoporotic fractures. Orthop. Surg. 2009 , 1 , 251–257. [ Google Scholar ] [ CrossRef ]
• Pietri, M.; Lucarini, S. The orthopaedic treatment of fragility fractures. Clin. Cases Miner. Bone Metab. 2007 , 4 , 108–116. [ Google Scholar ]
• Nyholm, A.M.; Gromov, K.; Palm, H.; Brix, M.; Kallemose, T.; Troelsen, A.; Collaborators, T.D.F.D. Time to Surgery Is Associated with Thirty-Day and Ninety-Day Mortality After Proximal Femoral Fracture: A Retrospective Observational Study on Prospectively Collected Data from the Danish Fracture Database Collaborators. J. Bone Jt. Surg. Am. 2015 , 97 , 1333–1339. [ Google Scholar ] [ CrossRef ]
• Maheshwari, K.; Planchard, J.; You, J.; Sakr, W.A.; George, J.M.; Higuera-Rueda, C.A.; Saager, L.M.; Turan, A.; Kurz, A. Early Surgery Confers 1-Year Mortality Benefit in Hip-Fracture Patients. J. Orthop. Trauma 2018 , 32 , 105–110. [ Google Scholar ] [ CrossRef ]
• Silverman, S.; Kupperman, E.; Bukata, S. Bisphosphonate-related atypical femoral fracture: Managing a rare but serious complication. Cleve Clin. J. Med. 2018 , 85 , 885–893. [ Google Scholar ] [ CrossRef ]
• Toro, G.; Ojeda-Thies, C.; Calabrò, G.; Toro, G.; Moretti, A.; Guerra, G.M.-D.; Caba-Doussoux, P.; Iolascon, G. Management of atypical femoral fracture: A scoping review and comprehensive algorithm. BMC Musculoskelet. Disord. 2016 , 17 , 227. [ Google Scholar ] [ CrossRef ]
• Babu, S.; Sandiford, N.A.; Vrahas, M. Use of Teriparatide to improve fracture healing: What is the evidence? World J. Orthop. 2015 , 6 , 457–461. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Miyakoshi, N.; Aizawa, T.; Sasaki, S.; Maekawa, S.; Aonuma, H.; Tsuchie, H.; Sasaki, H.; Kasukawa, Y.; Shimada, Y. Healing of bisphosphonate-associated atypical femoral fractures in patients with osteoporosis: A comparison between treatment with and without teriparatide. J. Bone Miner. Metab. 2015 , 33 , 553–559. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Shane, E.; Burr, D.; Abrahamsen, B.; Adler, R.A.; Brown, T.D.; Cheung, A.M.; Cosman, F.; Curtis, J.R.; Dell, R.; Dempster, D.W.; et al. Atypical subtrochanteric and diaphyseal femoral fractures: Second report of a task force of the American Society for Bone and Mineral Research. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2014 , 29 , 1–23. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Giusti, A.; Hamdy, N.A.T.; Papapoulos, S.E. Atypical fractures of the femur and bisphosphonate therapy: A systematic review of case/case series studies. Bone 2010 , 47 , 169–180. [ Google Scholar ] [ CrossRef ]
• FDA. FDA Drug Safety Communication: Safety Update for Osteoporosis Drugs, Bisphosphonates, and Atypical Fractures. 28 June 2019. Available online: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-update-osteoporosis-drugs-bisphosphonates-and-atypical (accessed on 14 February 2023).
• European Medicines Agency. EMA Bisphosphonates. 17 September 2018. Available online: https://www.ema.europa.eu/en/medicines/human/referrals/bisphosphonates (accessed on 14 February 2023).

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Share and Cite

Adejuyigbe, B.; Kallini, J.; Chiou, D.; Kallini, J.R. Osteoporosis: Molecular Pathology, Diagnostics, and Therapeutics. Int. J. Mol. Sci. 2023 , 24 , 14583. https://doi.org/10.3390/ijms241914583

Adejuyigbe B, Kallini J, Chiou D, Kallini JR. Osteoporosis: Molecular Pathology, Diagnostics, and Therapeutics. International Journal of Molecular Sciences . 2023; 24(19):14583. https://doi.org/10.3390/ijms241914583

Adejuyigbe, Babapelumi, Julie Kallini, Daniel Chiou, and Jennifer R. Kallini. 2023. "Osteoporosis: Molecular Pathology, Diagnostics, and Therapeutics" International Journal of Molecular Sciences 24, no. 19: 14583. https://doi.org/10.3390/ijms241914583

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• Patient Care & Health Information
• Diseases & Conditions
• Osteoporosis

Your bone density can be measured by a machine that uses low levels of X-rays to determine the proportion of mineral in your bones. During this painless test, you lie on a padded table as a scanner passes over your body. In most cases, only certain bones are checked — usually in the hip and spine.

More Information

• Bone density test

Treatment recommendations are often based on an estimate of your risk of breaking a bone in the next 10 years using information such as the bone density test. If your risk isn't high, treatment might not include medication and might focus instead on modifying risk factors for bone loss and falls.

Bisphosphonates

For both men and women at increased risk of broken bones, the most widely prescribed osteoporosis medications are bisphosphonates. Examples include:

• Alendronate (Binosto, Fosamax).
• Risedronate (Actonel, Atelvia).
• Ibandronate.
• Zoledronic acid (Reclast, Zometa).

Side effects include nausea, abdominal pain and heartburn-like symptoms. These are less likely to occur if the medicine is taken properly. Intravenous forms of bisphosphonates don't cause stomach upset but can cause fever, headache and muscle aches.

A very rare complication of bisphosphonates is a break or crack in the middle of the thighbone. A second rare complication is delayed healing of the jawbone, called osteonecrosis of the jaw. This can occur after an invasive dental procedure, such as removing a tooth.

Compared with bisphosphonates, denosumab (Prolia, Xgeva) produces similar or better bone density results and reduces the chance of all types of breaks. Denosumab is delivered via a shot under the skin every six months.

Similar to bisphosphonates, denosumab has the same rare complication of causing breaks or cracks in the middle of the thighbone and osteonecrosis of the jaw. If you take denosumab, you might need to continue to do so indefinitely. Recent research indicates there could be a high risk of spinal column fractures after stopping the drug.

Hormone-related therapy

Estrogen, especially when started soon after menopause, can help maintain bone density. However, estrogen therapy can increase the risk of breast cancer and blood clots, which can cause strokes. Therefore, estrogen is typically used for bone health in younger women or in women whose menopausal symptoms also require treatment.

Raloxifene (Evista) mimics estrogen's beneficial effects on bone density in postmenopausal women, without some of the risks associated with estrogen. Taking this drug can reduce the risk of some types of breast cancer. Hot flashes are a possible side effect. Raloxifene also may increase your risk of blood clots.

In men, osteoporosis might be linked with a gradual age-related decline in testosterone levels. Testosterone replacement therapy can help improve symptoms of low testosterone, but osteoporosis medications have been better studied in men to treat osteoporosis and thus are recommended alone or in addition to testosterone.

Bone-building medicines

If you have severe osteoporosis or if the more common treatments for osteoporosis don't work well enough, your doctor might suggest trying:

• Teriparatide (Bonsity, Forteo). This powerful drug is similar to parathyroid hormone and stimulates new bone growth. It's given by daily injection under the skin for up to two years.
• Abaloparatide (Tymlos) is another drug similar to parathyroid hormone. This drug can be taken for only two years.
• Romosozumab (Evenity). This is the newest bone-building medicine to treat osteoporosis. It is given as an injection every month at your doctor's office and is limited to one year of treatment.

After you stop taking any of these bone-building medications, you generally will need to take another osteoporosis drug to maintain the new bone growth.

• Osteoporosis treatment: Medications can help
• Vertebroplasty

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Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

These suggestions might help reduce your risk of developing osteoporosis or breaking bones:

• Don't smoke. Smoking increases rates of bone loss and the chance of fracture.
• Limit alcohol. Consuming more than two alcoholic drinks a day may decrease bone formation. Being under the influence of alcohol also can increase your risk of falling.
• Prevent falls. Wear low-heeled shoes with nonslip soles and check your house for electrical cords, area rugs and slippery surfaces that might cause you to fall. Keep rooms brightly lit, install grab bars just inside and outside your shower door, and make sure you can get into and out of your bed easily.

Preparing for your appointment

Your health care team might suggest bone density testing. Screening for osteoporosis is recommended for all women over age 65. Some guidelines also recommend screening men by age 70, especially if they have health issues likely to cause osteoporosis. If you have a broken bone after a minor force injury, such as a simple fall, bone density testing may be important to assess your risk of more breaks.

If the test results show very low bone density or you have other complex health issues, you might be referred to a provider who specializes in metabolic disorders, called an endocrinologist, or a provider who specializes in diseases of the joints, muscles or bones, called a rheumatologist.

Here's some information to help you get ready for your appointment.

What you can do

• Write down symptoms you've noticed, though it's possible you may not have any.
• Write down key personal information, including major stresses or recent life changes.
• Make a list of all medicines, vitamins and supplements that you take or have taken, including doses. It's especially helpful if you record the type and dose of calcium and vitamin D supplements, because many different preparations are available. If you're not sure what information your doctor might need, take the bottles with you or take a picture of the label with your smartphone and share it with your doctor.
• Write down questions to ask your health care provider.

For osteoporosis, basic questions to ask your provider include:

• Do I need to be screened for osteoporosis?
• What treatments are available, and which do you recommend?
• What side effects might I expect from treatment?
• Are there alternatives to the treatment you're suggesting?
• I have other health problems. How can I best manage them together?
• Do I need to restrict my activities?
• Do I need to change my diet?
• Do I need to take supplements?
• Is there a physical therapy program that would benefit me?
• What can I do to prevent falls?

Don't hesitate to ask other questions.

What to expect from your doctor

Your provider is likely to ask you questions, such as:

• Have you broken bones?
• Have you gotten shorter?
• How is your diet, especially your dairy intake? Do you think you get enough calcium? Vitamin D?
• How often do you exercise? What type of exercise do you do?
• How is your balance? Have you fallen?
• Do you have a family history of osteoporosis?
• Has a parent broken a hip?
• Have you ever had stomach or intestinal surgery?
• Have you taken corticosteroid medicines, including prednisone, cortisone, as pills, injections or creams?
• Osteoporosis overview. National Institute of Arthritis and Musculoskeletal and Skin Diseases. https://www.bones.nih.gov/health-info/bone/osteoporosis/overview. Accessed June 3, 2021.
• Osteoporosis. Merck Manual Professional Version. https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/osteoporosis/osteoporosis?query=osteoporosis. Accessed June 3, 2021.
• Kellerman RD, et al. Osteoporosis. In: Conn's Current Therapy 2021. Elsevier; 2021. https://www.clinicalkey.com. Accessed June 3, 2021.
• Ferri FF. Osteoporosis. In: Ferri's Clinical Advisor 2021. Elsevier; 2021. https://www.clinicalkey.com. Accessed June 3, 2021.
• Goldman L, et al., eds. Osteoporosis. In: Goldman-Cecil Medicine. 26th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed June 3, 2021.
• Calcium fact sheet for health professionals. Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional. Accessed June 8, 2021.
• Vitamin D fact sheet for health professionals. Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional. Accessed June 8, 2021.
• Rosen HN, et al. Overview of the management of osteoporosis in postmenopausal women. https://www.uptodate.com/contents/search. Accessed June 3, 2021.
• Compression fractures
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• Osteoporosis weakens bone

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