Approach

The main goal of treatment is prevention of fractures, particularly hip, vertebral, and radial fractures. The approach to treatment is population-specific, but exercise and adequate calcium and vitamin D intake (with supplementation if needed) are recommended for all people with osteoporosis.[62][70]​​​​

Diet and lifestyle

Calcium and vitamin D

Patients with osteoporosis should be advised to consume the recommended daily allowance of calcium and vitamin D through diet, supplementation, or both.[62][70]​​​ Adequate calcium intake is necessary to maintain bone health, and vitamin D facilitates dietary calcium absorption.[62]​​

​Evidence of the effect of calcium and vitamin D supplementation on fracture risk is mixed. One systematic review demonstrated that calcium and vitamin D supplementation significantly reduced the incidence of fractures and enhanced bone mineral density (BMD) in older adults compared with the control group.[92]​ Another systematic review of randomised controlled trials (RCTs) and observational studies of calcium intake with fractures as an end point showed that dietary calcium intake is not associated with risk of fractures, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Moreover, evidence that calcium supplements prevent fractures was weak and inconsistent.[93] In subsequent letters to the editors, it is argued that the results of these trials cannot be applied to a specifically targeted frail, older population that may benefit from calcium supplementation.

One meta-analysis of 16 RCTs suggests that calcium supplementation without vitamin D increases the risk of myocardial infarction by approximately 21%.[94]​ One re-analysis of the Women's Health Initiative (WHI) Calcium/Vitamin D supplementation study (WHI CaD study), in conjunction with a meta-analysis of 8 other studies investigating the association between calcium ± vitamin D supplementation and cardiovascular risk, reports that calcium supplements, with or without vitamin D, modestly increase the risk of cardiovascular events (especially myocardial infarction), a finding earlier obscured in the WHI CaD study by the widespread use of personal calcium supplements.[95]

On the contrary, another 5-year RCT in 1460 women with a mean age of 75 years showed that calcium supplementation without vitamin D did not increase the risk of death or first-time hospitalisation from atherosclerotic vascular disease.[96][97]

Adverse effects of calcium supplements are primarily gastrointestinal. The WHI study found increased moderate to severe constipation, bloating, and wind.[35] However, these symptoms did not differ statistically from the placebo group. Nephrolithiasis may also occur.[35]

Exercise

For those who are able, regular weight-bearing exercise is recommended to maintain bone strength, and exercises that enhance balance may help to prevent falls.[62][81]​​[98]​​​​​ Guidelines recommend progressive muscle resistance training plus balance and functional training at least 2 days per week for fall and fracture prevention.[98]​​[99]​ Patients with vertebral fractures, multiple low-trauma fractures, or frailty may have a higher risk of injury and require tailored advice and supervision.[98]

Evidence from systematic reviews has demonstrated that patients with osteoporosis may safely participate in exercise programmes, and that exercise may improve BMD and reduce the risk of falls.​[100]​​​​[101][102][103]​​​​​ However, the exact type of activity and its intensity, duration, and frequency are still unclear.[101][104][105]​​​​​​​​​[106]​ Supervised exercise programmes may reduce the risk of fractures more effectively.​​​​[107]

Pharmacological treatment

Two categories of drugs are used for the management of osteoporosis. One class inhibits bone resorption (antiresorptive drugs) and the other stimulates bone formation (anabolic drugs).[62] Antiresorptive drugs include bisphosphonates, oestrogen, selective oestrogen receptor modulators (SERMs), and denosumab. Anabolic drugs include parathyroid hormone analogues (e.g., teriparatide, abaloparatide) and romosozumab. Choice of treatment depends on the patient group (men vs. women) and whether osteoporosis is corticosteroid-induced.

Postmenopausal women

Before starting pharmacotherapy for osteoporosis, secondary causes of bone loss should be excluded; pharmacotherapy for postmenopausal osteoporosis is recommended for patients who are at high risk of fracture, who meet any of these criteria:[62][70]​​​​​[108]​​​​​​​​​​​​​​​​​ 

  • T-score -2.5 or lower by dual-energy x-ray absorptiometry (DXA) of the femoral neck, total hip, lumbar spine, or 33% radius

  • History of fragility fracture, including asymptomatic vertebral fracture

  • T-score between -1.0 and -2.5 and increased risk of fracture, as determined by a formal clinical risk assessment tool

​If patients meet these criteria, consideration of the use of osteoporosis pharmacotherapy in postmenopausal women should include the following:[70]

  • Type of treatment

  • Timing of initiation

  • Length of treatment

  • Use of drug holidays to reduce the adverse effects

  • Bone loss management when therapy is discontinued

  • Timing of therapy reinitiation

  • Indications for referral to an endocrinologist or other osteoporosis specialist

[Figure caption and citation for the preceding image starts]: Management of postmenopausal women with non-glucocorticoid-induced osteoporosisCreated by BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@6d40092c

Bisphosphonates

Bisphosphonates (e.g., alendronic acid, ibandronic acid, risedronate, and zoledronic acid) are indicated for the treatment of osteoporosis in postmenopausal women.[70][109]​​​​​​​​​​​​​​​ They effectively increase BMD and decrease risk of vertebral and non-vertebral fractures.​[110][111]​​​​​​​​​​​​​​​​​​ This is with the exception of ibandronic acid, which has only been shown to decrease the risk of femoral fracture in high-risk populations with a femoral neck BMD T-score of -3 or less by post-hoc analysis.[112]

Bisphosphonates are the first-line treatment for postmenopausal women at high risk of fracture with prior hip or vertebral fractures and/or DXA T-score of ≤-2.5. It is recommended that treatment commences at the time of diagnosis.[62][67]​​[70]​​​​​​[108]​​​ Bisphosphonates may also be used for women with a very high risk of fracture (e.g., very low T-score and a history of severe or multiple vertebral fractures, a recent fracture, or multiple risk factors for fracture), but guidelines recommend initial treatment with an anabolic agent as the preferred option for these patients.[67][70][81]​​​[113]​​[114]

Oral bisphosphonates reduce the risk of fracture in women with prior fragility fractures.[115][116]​​​​​​​​​​​​​​

​A drug holiday for patients with a low to moderate risk of fracture should be considered for patients:[70]​

  • who are stable after 5 years of treatment with oral bisphosphonates, or

  • after 3 years of treatment with zoledronic acid.

For patients at high risk of fracture, longer treatment of up to 10 years with oral bisphosphonates or up to 6 years with zoledronic acid is suggested.[70]​ 

Adverse effects of oral bisphosphonates primarily relate to the upper gastrointestinal tract and include difficulty swallowing, oesophagitis, and gastric ulcers. Joint and muscular pain, osteonecrosis of the jaw, and atypical femoral fractures have also been reported.[117][118][119][120][121][122]​​​​​​​​​​​​​​​​ One large systematic review and meta-analysis of more than 650,000 patients demonstrated an increased risk of atypical fractures with bisphosphonates.[119] Further research concluded that the benefits of bisphosphonate treatment outweigh the risk of atypical femur fracture, particularly in patients treated for 3-5 years.[123]​ Consensus is emerging about strategies to prevent atypical femur fracture in patients treated with bisphosphonates, including drug holidays after 5 years' use in some patients.[123]

Alendronic acid and risedronate:[124][125]​​​​​[126][127][128][129]​​​​​​

  • Alendronic acid and risedronate were the first bisphosphonates approved for treatment of postmenopausal osteoporosis and remain among the most commonly prescribed osteoporosis treatments. Both have been shown to reduce the risk of vertebral, non-vertebral, and hip fractures.

  • In one placebo-controlled extension trial, women who continued alendronic acid treatment for 10 years had a significantly lower risk of clinically recognised vertebral fractures compared with those who discontinued alendronic acid after 5 years.​ The risk of non-vertebral fractures was not significantly different between the two groups overall, but a post-hoc analysis found that continuing alendronic acid for 10 years reduced the risk of non-vertebral fractures in a sub-group of women with a T-score of ≤-2.5 and no vertebral fractures after 5 years of treatment. There was no benefit to continuing alendronic acid beyond 5 years in those with a T-score >-2.0.

  • Analysis of the Vertebral Efficacy with Risedronate Therapy (VERT) trials suggests that risedronate reduces the risk of vertebral fractures within 6 months of treatment. Clinical trials support the sustained efficacy of risedronate through 5-7 years of treatment and a continued anti-fracture benefit for 1 year after stopping treatment.

​Ibandronic acid:[108][130][131]​​

  • May reduce vertebral fracture but its effects in reducing hip fracture and non-vertebral fracture are uncertain, and it is therefore not recommended for these indications in postmenopausal women.

  • Intravenous ibandronic acid has been shown to be effective in increasing BMD in the treatment and prevention of postmenopausal osteoporosis.​

Zoledronic acid:[132][133][134][135][136][137][138]​​​​​​[139]​​[140]

  • One study demonstrated that 6 years of treatment with zoledronic acid maintained BMD, decreased vertebral fracture, and reduced bone turnover markers compared with 3 years of treatment in patients with osteoporosis. In an extension study, those who were treated with zoledronic acid for 6 years were randomised to either continue zoledronic acid for a further 3 years or switched to placebo. The extension study found no significant decrease in the number of fractures between the two groups. In an observational follow-up of older women with osteopenia randomised to receive zoledronic acid or placebo at 18-month intervals for 6 years, reduced fracture rates were maintained for 1.5 to 3.5 years after the last zoledronic acid infusion, but were similar to the placebo group thereafter.

  • Zoledronic acid exerts a faster effect in the prevention of vertebral fractures and a slower onset effect in the prevention of hip fractures.​​

  • Conflicting results have been reported concerning the risk of serious atrial fibrillation in women treated with zoledronic acid. Systematic reviews of RCTs and observational studies showed significantly increased risk of new-onset atrial fibrillation with both intravenous and oral bisphosphonates. However, studies did not show evidence of increased comorbidities such as stroke or death. Overall, the risk-benefit balance outweighs such complications in this population.

Denosumab

Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), a cytokine that is involved in mediating osteoclast activity.

It is approved for the treatment of:

  • Postmenopausal women with osteoporosis who are at high risk for fracture

  • Osteoporosis prophylaxis in women at high risk for fracture after receiving adjuvant aromatase inhibitor therapy for breast cancer.

Denosumab may also be used for women with a very high risk of fracture (e.g., very low T-score and a history of severe or multiple vertebral fractures, a recent fracture, or multiple risk factors for fracture), but guidelines recommend initial treatment with an anabolic agent as the preferred option for these patients.[67][70][81]​​​​[113]​​[114]​​​​​ 

Denosumab should be used with caution in patients with pre-existing hypocalcaemia or who are at high risk of hypocalcaemia (vitamin D deficient), and in patients with severe renal disease, including end-stage renal disease.[62][108] The US Food and Drug Administration (FDA) has warned of an increased risk of severe hypocalcaemia in patients with advanced chronic kidney disease who are receiving denosumab.[141]​ Two safety studies showed a significant increase in the risk of severe hypocalcaemia in patients treated with denosumab compared with those treated with bisphosphonates, with the highest risk reported in patients with advanced kidney disease, particularly those on dialysis.[141][142]​​​​ Severe hypocalcaemia was more common in those with a mineral and bone disorder. Patients with advanced chronic kidney disease taking denosumab are at risk of serious outcomes from severe hypocalcaemia, including hospitalisation and death. Before prescribing denosumab, healthcare professionals should assess kidney function and calcium levels, and consider other treatment options for patients at risk. During treatment, frequent monitoring and prompt management of hypocalcaemia are essential.

​The American College of Obstetrics and Gynecology recommends:[70]​  

  • Denosumab as initial therapy for postmenopausal patients at increased risk of fracture who prefer 6-monthly subcutaneous administration

  • Patients who discontinue denosumab therapy should be transitioned to treatment with another antiresorptive agent.

​The Endocrine Society recommends:[108]

  • Denosumab as an alternative initial treatment in postmenopausal women with osteoporosis who are at high risk for osteoporotic fractures.

  • The effects of denosumab on bone remodelling, reflected in bone turnover markers, reverse after 6 months if the drug is not taken on schedule. Therefore, a drug holiday or treatment interruption is not recommended with this agent.

  • In postmenopausal women with osteoporosis taking denosumab, administration should not be delayed or stopped without subsequent antiresorptive therapy (e.g., bisphosphonate, hormone therapy, or SERM) or other therapy administered to prevent a rebound in bone turnover and to decrease the risk of rapid BMD loss and an increased risk of fracture.

  • Fracture risk should be reassessed after 5-10 years of treatment and those women with a high risk of fracture should continue treatment with denosumab or be treated with other osteoporotic treatment.

The American College of Physicians recommends denosumab as a second-line treatment to reduce the risk of fracture in postmenopausal women with primary osteoporosis who have contraindications to or experience adverse effects with bisphosphonates.[67]

The FREEDOM trial demonstrated that denosumab given for 36 months was associated with reduction in the risk of vertebral, non-vertebral, and hip fractures in women with osteoporosis who had a BMD T-score of -2.5 but not less than -4.0 at the lumbar spine or total hip, compared with placebo.[143]

​Extension studies of the FREEDOM trial reported that:[144][145]​​​​​​​​​​[146]​  

  • Denosumab treatment of postmenopausal osteoporosis for up to 8 years was associated with persistent reduction of bone turnover, continued increase in BMD, low fracture incidence, and high benefit-risk profile

  • Denosumab treatment for up to 10 years was associated with low rates of adverse events, low incidence of fracture compared with that observed during the original trial, and continued increases in BMD without plateau

  • Discontinuation of denosumab is followed by rapidly rising turnover markers, decreasing bone density, and increasing vertebral fracture risk, suggesting that patients who discontinue denosumab should transition quickly to an alternative antiresorptive treatment.

There is some evidence to suggest that zoledronic acid given after denosumab is most effective 7-8 months post denosumab discontinuation, and that teriparatide given either prior to or in combination with denosumab increases BMD.[147][148][149]​​​​​​​​​​​​​ However, further research is needed.[62]

Denosumab has been reported to be significantly more effective at increasing BMD in postmenopausal women previously treated with bisphosphonates, and has demonstrated significant improvement of BMD in at the lumbar spine, total hip, and femoral neck at 12 and 24 months in patients with low BMD or osteoporosis, compared with bisphosphonates.[150][151]​​​​​​​​​ In patients aged 50 years and older with osteoporosis, denosumab was found to be as effective as zoledronic acid at reducing the risk of fractures.[152]​ 

An increased risk of serious infection has been reported in patients treated with denosumab compared with placebo.[153][154]​​​​​​​​ However, the overall risk of infection is comparable with other osteoporosis treatments, including bisphosphonates.[153][154]​​​​​​​​ Denosumab has been associated with osteonecrosis of the jaw, impairment of fracture healing, and atypical femoral fractures.[62][67]​​​​​​​​

Denosumab is not associated with increased risk of cardiovascular outcomes compared with placebo or active comparators.[152][155]​​​​​​ 

Anabolic agents

Anabolic agents include teriparatide, abaloparatide, and romosozumab.

Teriparatide and abaloparatide are parathyroid hormone analogues approved to treat osteoporosis in postmenopausal women. Teriparatide is a recombinant form of parathyroid hormone, while abaloparatide is an analogue of human parathyroid hormone-related peptide.

Romosozumab, a monoclonal antibody sclerostin inhibitor that decreases bone resorption and increases bone formation, is approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture (defined as a history of osteoporotic fracture, or multiple risk factors for fracture), or patients who have failed or are intolerant to other available osteoporosis therapy.

Guidelines recommend initial treatment with an anabolic agent for postmenopausal women with a very high risk of fracture, such as those with a very low T-score and a history of severe or multiple vertebral fractures, a recent fracture, or multiple risk factors for fracture.[62][67]​​[70][81]​​[108]​​[113]​​​​​​ The American College of Obstetrics and Gynecology (ACOG) recommends that teriparatide, abaloparatide, or romosozumab may also be used for those who continue to sustain fractures or have significant bone loss while taking antiresorptive therapy.[70]

One meta-analysis found that teriparatide and romosozumab were more effective than oral bisphosphonates for reducing risk of clinical and vertebral fractures regardless of baseline fracture risk indicators (history of previous fractures, age, spine T-score, body mass index [BMI], Fracture Risk Assessment Tool [FRAX] score for major osteoporotic fractures).[156]​ However, guidelines suggest initial treatment with an anabolic agent may be most beneficial for patients with a very high risk of fractures in practice, in part because anabolic agents require subcutaneous administration.[81][157]​​​ Anabolic agents are not typically used as initial therapy in patients with a high risk of fractures.

The American College of Physicians (ACP) guideline only recommends teriparatide or romosozumab for women with primary osteoporosis and a very high risk of fracture; they concluded that evidence for or against abaloparatide treatment was inconclusive.[67]​ The ACP suggests that postmenopausal women with prevalent vertebral fractures benefit more from teriparatide treatment than those without prevalent fractures.[67]

The Royal Australian College of General Practitioners guideline recommends romosozumab as the preferred first-line option for patients with a very high risk of fracture, based on evidence that it may increase BMD more effectively than alendronic acid or teriparatide.[81]

Romosozumab:[67][81]​​[108][113]​​​[158][159][160][161][162][163][164][165][166]

  • Romosozumab is recommended for the treatment of postmenopausal osteoporosis for up to 1 year. Romosozumab should be avoided in patients with a high risk for cardiovascular disease or stroke.​

  • Treatment with romosozumab should be followed by sequential therapy with an antiresorptive agent to maintain BMD gains and reduce the risk of fracture.

  • Romosozumab has demonstrated significant reductions in new vertebral fractures, new non-vertebral fractures, and hip fracture compared with other osteoporosis therapies, and an increase in BMD at lumbar spine, total hip, and femoral neck compared with placebo in postmenopausal women and other patients with osteoporosis and low BMD.

  • A subsequent systematic review reported that romosozumab increased BMD at the lumbar spine and total hip compared with teriparatide at 12 months in patients with osteoporosis. In postmenopausal women at a higher risk of fracture, 1 year of romosozumab followed by 1 year of alendronic acid reduced the risk of vertebral, non-vertebral, clinical, and hip fractures compared with alendronic acid alone at 24 months. Cardiovascular and cerebrovascular events were higher in the romosozumab group compared with alendronic acid.

  • Some evidence suggests that romosozumab may have a lower rate of adverse effects compared with alendronic acid and a similar safety profile to bisphosphonates; however, most studies agree that further research is needed to establish the risk of cardiovascular disease with romosozumab treatment.

Teriparatide and abaloparatide:[62][70]​​​[108][167][168][169][170][171][172][173][174][175][176]

  • Guidelines recommend treatment with teriparatide or abaloparatide for up to 2 years. Teriparatide treatment for more than 2 years can be considered if the patient remains or returns to having a high risk of fracture.

  • The Bone Health and Osteoporosis Foundation (BHOF) suggests that teriparatide and abaloparatide should be avoided in patients at an increased risk of osteosarcoma (Paget's disease of the bone, prior radiotherapy involving the skeleton, history of bone metastases or malignancies, unexplained elevated alkaline phosphatase, and hereditary disorders predisposing to osteosarcoma).

  • When treatment is stopped, bone loss can be rapid and alternative agents should be considered to maintain BMD. The BHOF and the Endocrine Society recommend that teriparatide or abaloparatide treatment is followed with an antiresorptive agent, usually a bisphosphonate, to maintain or further increase BMD.

  • Clinical trials have demonstrated that teriparatide increases BMD in comparison with placebo. Evidence of the effectiveness of teriparatide in comparison with other treatments for osteoporosis varies. One systematic review demonstrated that teriparatide improves BMD in lumbar spine, femoral neck, and total hip, and reduces the incidence of clinical fracture, new vertebral fracture, and non-vertebral fracture compared with risedronate. Conversely, a network meta-analysis suggests that teriparatide is less effective compared with other drugs such as bisphosphonates, denosumab, or romosozumab at reducing fracture risk in patients with osteoporosis. Two further systematic reviews demonstrated that teriparatide was less effective than romosozumab at improving BMD of lumbar spine, total hip, and femoral neck for patients with postmenopausal osteoporosis at 6 and 12 months.

  • The ACTIVE phase 3 double-blind controlled trial and subsequent extension trials demonstrated that abaloparatide reduced the risk of new vertebral and non-vertebral fractures over 18 months compared with placebo, and that sequential use of alendronic acid for 6 or 24 months post abaloparatide treatment reduced the risk of vertebral, non-vertebral, clinical, and major osteoporotic fractures and increased BMD compared with placebo in postmenopausal women.

  • Results from network meta-analyses indicate that abaloparatide reduces the risk of vertebral fracture, non-vertebral fracture, and wrist fracture compared with other treatments for osteoporosis such as teriparatide, romosozumab, or ibandronic acid in patients with osteoporosis, including postmenopausal women.

  • Adverse effects of teriparatide include leg cramps, nausea, and dizziness, and for abaloparatide they include nausea, postural hypotension, dizziness, headache, and palpitations.

SERMs

SERMs include raloxifene and bazedoxifene.

Raloxifene is approved for the treatment and prevention of osteoporosis in postmenopausal women. It increases BMD at the spine but to a lesser degree than bisphosphonates, and is only effective in lowering vertebral fracture.[125] Raloxifene reduces the risk of vertebral fractures in postmenopausal women with osteoporosis.[177] There is no evidence for reduction of non-vertebral fractures.

Raloxifene use is associated with an increased risk of venous thrombosis and stroke.[62] Possibility of adverse effects is weighed against potential benefits of reduced risk of vertebral fracture and oestrogen receptor-positive breast cancer.

The ACOG suggests raloxifene for postmenopausal patients at increased risk of vertebral fracture and breast cancer who are at low risk of venous thromboembolism and do not have significant vasomotor symptoms.[70]

The Endocrine Society recommends raloxifene or bazedoxifene to reduce the risk of vertebral fracture in postmenopausal women aged under 60 years or <10 years past menopause, with osteoporosis at high risk of fracture and who have a low risk of deep vein thrombosis, and for whom bisphosphonates or denosumab are not appropriate, or have a high risk of breast cancer.[108]

The ACP concluded that there is insufficient evidence to recommend for or against treatment with raloxifene or bazedoxifene.[67]

One systematic review demonstrated that raloxifene is effective at improving lumbar spine BMD in postmenopausal women with end-stage renal disease compared with placebo, with a mean duration of treatment of 12 months.[178] No adverse effects were reported in the raloxifene patient group, but further large RCTs are needed to evaluate the long-term safety of raloxifene in these patients.[178]

Bazedoxifene reduces the risk of endometrial hyperplasia (excessive growth of the lining of the uterus) that can occur with oestrogen treatment.​[179]

Bazedoxifene is only available in a combination formulation with conjugated oestrogens in the US; however, it is available as a single-ingredient formulation in other countries. Conjugated oestrogens/bazedoxifene is recommended third-line only after careful consideration of alternative agents that do not contain oestrogen (see below).[62]

Hormone therapy

Oestrogen decline at menopause is strongly associated with the decrease in BMD.[2]​​[3]

There are various forms of hormone replacement therapy (HRT). Oestrogen, either alone or in combination with a progestin, is considered only for women at high risk of osteoporotic fractures for whom non-hormonal therapy is inappropriate.

HRT reduces the incidence of fracture. However, there are considerable increases in risk of coronary heart disease, breast cancer, venous thrombosis, and stroke.[180][181][182]

The WHI report assessed the efficacy of conjugated oestrogens versus placebo in 10,739 postmenopausal women, aged 50-79 years with prior hysterectomy.[183] The primary outcome was coronary heart disease. The study reported that conjugated oestrogens increased the risk of stroke, decreased the risk of hip fracture, and did not affect the incidence of coronary heart disease in this population at an average of 6.8 years.[183]

The Endocrine Society recommends oestrogen as first-line treatment to prevent all types of fracture for women (under 60 years of age or <10 years past menopause) with hysterectomy at high risk of osteoporotic fracture, with a low risk of deep vein thrombosis, for whom bisphosphonates or denosumab are not appropriate, who have vasomotor symptoms, who have no contraindications, no prior myocardial infarction, stroke, or breast cancer, and are willing to take menopausal hormone therapy.[108]

Women who have a uterus should use oestrogen only in combination with a progestin because using oestrogen alone increases the incidence of endometrial cancer.[184]

The Endocrine Society recommends oestrogen plus a progestin or tibolone (not available in the US) as first-line treatment to prevent vertebral and non-vertebral fractures for women aged under 60 years (or <10 years past menopause) at high risk of osteoporotic fracture, with a low risk of deep vein thrombosis, for whom bisphosphonates or denosumab are not appropriate, who have vasomotor symptoms, who have no contraindications, no prior myocardial infarction, stroke, or breast cancer, and are willing to take menopausal tibolone therapy.[108]

The Endocrine Society also recommends oestrogen plus a progestin or tibolone as second-line treatment to prevent vertebral and non-vertebral fractures for women aged over 60 years for whom bisphosphonates, denosumab, and teriparatide/abaloparatide are not appropriate.[108]

The ACP recommends against using menopausal oestrogen alone or in combination with progestin therapy for the treatment of osteoporosis in women.[185]

Conjugated oestrogens/bazedoxifene

Conjugated oestrogens/bazedoxifene are indicated for osteoporosis prophylaxis due to menopause in women with an intact uterus.[62][70]​​​​​​ Bazedoxifene on its own is indicated for the treatment of postmenopausal osteoporosis in women at increased risk of fracture, but it is not available as a single-ingredient formulation in the US.

The BHOF recommends conjugated oestrogens/bazedoxifene for the prevention of osteoporosis only in women at significant risk of fracture and only after careful consideration of alternative treatments that do not contain oestrogen.[62]​ This treatment should only be used for the shortest duration consistent with treatment goals and risks for the individual woman.[62]

Adverse effects include muscle spasms, nausea, diarrhoea, dyspepsia, upper abdominal pain, oropharyngeal pain, dizziness, and neck pain.[62]

Men

Men aged 50 years and older presenting with any of the following should be considered for osteoporosis treatment:[62]

  • A hip or vertebral fracture (clinically apparent or found on vertebral imaging) regardless of T-score

  • A fracture of the pelvis, proximal humerus, or distal forearm in a person with low bone mass or osteopenia

  • T-score ≤-2.5 at the femoral neck, total hip, lumbar spine, or 33% radius

  • High fracture risk and need for pharmacological intervention as indicated by T-score between -1.0 and -2.5 at the femoral neck or total hip and a 10-year probability of a hip fracture ≥3% or a 10-year probability of a major osteoporosis-related fracture ≥20% (based on FRAX).

Bisphosphonates

Oral bisphosphonates are the preferred first-line treatment for men with osteoporosis and a high risk of fracture, with or without prior vertebral fracture.[82]​ Alendronic acid, risedronate, and zoledronic acid are approved for the treatment of osteoporosis in men.​ However, despite significant understanding of the pathogenesis and management of male osteoporosis, several key issues remain unresolved. In the US, the FDA has not approved the use of zoledronic acid for men with osteoporosis and testosterone deficiency.

A multicentre, double-blind, placebo-controlled trial of men with primary and hypogonadism-associated osteoporosis aged 50-85 years found that an intravenous infusion of zoledronic acid at baseline and 12 months reduces the risk of new morphometric vertebral fracture by 67% over a 24-month period compared with placebo.[186]

The ACP guideline indicates that the response to bisphosphonate and denosumab treatment is similar in men as well as in women.[67]​​

Adverse effects of oral bisphosphonates primarily relate to the upper gastrointestinal tract and include difficulty swallowing, oesophagitis, and gastric ulcers. Joint and muscular pain, osteonecrosis of the jaw, and atypical femoral fractures have also been reported.[117][118][119][120][121][122]

Testosterone

Testosterone deficiency has been associated with decreased BMD in men, but evidence that testosterone replacement therapy improves BMD or reduces the risk of fractures is limited and inconsistent.[82]​

One systematic review concluded that testosterone therapy did not increase BMD in the spine, the femoral neck, Ward’s triangle, and the whole body, with the exception of the trochanter and total hip in older men.[187]​ Testosterone therapy may be considered as an adjunct to osteoporosis-specific therapy in patients with symptomatic testosterone deficiency.[82][188]​​ It is not recommended for men with normal testosterone levels.

Anabolic agents

Some guidelines recommend considering initial treatment with an anabolic agent (e.g., teriparatide, abaloparatide, romosozumab) for men with a very high risk of fractures.[81][82]​​​ This should be followed by sequential therapy with an antiresorptive agent.[82]​ However, although the ACP guideline recommends this approach for women with a very high risk of fractures, they concluded that evidence was insufficient to make a similar recommendation for men.[67]

Guidelines suggest initial treatment with an anabolic agent may be most beneficial for patients with a very high risk of fractures in practice, and they are not typically used as initial therapy in patients with a high risk of fractures.[81][99]​​[157]​​

Teriparatide and abaloparatide are approved for men with a high fracture risk.[189] ​ Abaloparatide significantly increases BMD at the lumbar spine, total hip, and femoral neck compared with placebo in men with osteoporosis.[190][191] European guidelines for osteoporosis in men concluded that evidence of BMD improvement is strongest for abaloparatide.​​​[82]​ In the UK, teriparatide is recommended as an alternative treatment option for the secondary prevention of osteoporotic fractures in men.[192]

RCTs in men with osteoporosis report that teriparatide increases BMD at the spine and femoral neck.[193] Although BMD gradually decreases after discontinuation of treatment, when followed by antiresorptive treatment, teriparatide decreases the risk of moderate and severe vertebral fracture.[194]

Evidence also suggests that teriparatide is as effective in men as in postmenopausal women to treat osteoporosis.[195]

When treatment with teriparatide or abaloparatide is stopped, bone loss can be rapid and alternative agents should be considered to maintain bone mineral density.[62][82]

Romosozumab is not approved for use in men with osteoporosis in the US or Europe, but it is approved in some other countries to treat men with osteoporosis at high risk of fracture.[62]​ Romosozumab treatment for 12 months resulted in significantly higher BMD at the spine, femoral neck, and total hip compared with placebo, and was well tolerated in men with osteoporosis.[196]

Denosumab

Denosumab is approved for the treatment of men with osteoporosis who are at high risk of fractures, defined as a history of fragility factors, or multiple risk factors for fractures; or those who failed or are intolerant to other available osteoporosis drug regimens (see the FDA warning in the information on denosumab in the postmenopausal women section).

It is also approved for osteoporosis prophylaxis in men at high risk for fracture after receiving androgen deprivation therapy for non-metastatic prostate cancer. In men with non-metastatic prostate cancer, denosumab also reduced the incidence of vertebral fracture.[197]

Glucocorticoid-induced osteoporosis

Corticosteroid-induced osteoporosis is a complex disorder that encompasses both increased bone resorption and defective bone formation. Bone fracture occurs in 30% to 50% of patients receiving chronic corticosteroid treatment; therefore, its prevention and treatment is imperative in this population.[65]​​ Patients receiving long-term corticosteroids should be assessed for fracture risk at initiation of therapy and every 1-2 years while corticosteroid treatment continues.[87]​ ​Treatment and prevention of corticosteroid induced osteoporosis is based on age and risk of fracture, ranging from low to very high risk. See Diagnostic criteria.

[Figure caption and citation for the preceding image starts]: Management of glucocorticoid-induced osteoporosisCreated by BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@613c7246

Lifestyle changes and supplements

The American College of Rheumatology (ACR) recommends all adults taking prednisolone at a dose of ≥2.5 mg/day for ≥3 months should optimise calcium and vitamin D intake (with supplementation if needed) and make lifestyle modifications (e.g., balanced diet, maintaining weight in the recommended range, smoking cessation, regular weight‐bearing or resistance training exercise, limiting alcohol intake to 1-2 alcoholic beverages per day).[87]​​ These measures should be used in combination with pharmacological interventions for patients with moderate to very high risk of fracture, however no further treatment is recommended for patients with low fracture risk.​[87]

Bisphosphonates

Bisphosphonate use should be considered for most patients with corticosteroid treatment continuing >3 months, receiving from 2.5 to ≥7.5 mg/day of prednisolone, and in those with a history of prior fracture.[24]​​[66]

The ACR recommends oral or intravenous bisphosphonates for adults at moderate, high risk, or very high risk of fracture who are receiving long-term corticosteroids.[87]​ For adults aged ≥40 years at high or very high risk of fracture, bisphosphonates are conditionally recommended second-line based on evidence of superior BMD improvements with parathyroid hormone analogues and denosumab.[87]​​ Patients with chronic kidney disease (eGFR <35 mL/minute) should generally not be treated with bisphosphonates.​[87]

For women of childbearing age who are not planning a pregnancy during osteoporosis treatment, an oral or intravenous bisphosphonate is recommended, but should be used with caution due to potential adverse effects to fetal bones.​[87]

Patients treated with oral or intravenous bisphosphonates who have a low to moderate risk of fracture and discontinue corticosteroid treatment do not require sequential therapy.[87]​ However, if a new fracture occurs after ≥12 months of initial bisphosphonate therapy, sequential therapy may include denosumab, parathyroid hormone analogue or romosozumab.​[87]

If treated with denosumab sequential therapy, patients will require additional therapy with bisphosphonates 6-7 months after the last dose of denosumab to prevent rapid bone loss and development of new vertebral compression fractures.​[87]

The bisphosphonates alendronic acid and risedronate have been shown to effectively reduce bone fracture for patients with corticosteroid induced osteoporosis.[198] [ Cochrane Clinical Answers logo ] [Evidence A]

Parathyroid hormone analogues

The ACR recommend a parathyroid hormone analogue (e.g., teriparatide, abaloparatide) as a first-line option for the treatment of adults ≥40 years with high to very high risk of fracture, including patients on very high-dose corticosteroid treatment (initial prednisolone dose ≥30 mg/day or cumulative prednisolone dose ≥5 g in 1 year).[87]​​ For patients with a moderate risk of fracture, a parathyroid hormone analogue may be considered as an alternative option.[24][199]​ The ACR recommends them as an equal first-line option for adults with a moderate risk of fracture, and emphasises shared decision-making for choice of initial therapy, considering clinician and patient preferences and comorbidities.​​​[87]Parathyroid hormone analogues should be avoided for the treatment of young adults with open growth plates.​[87]​​

Teriparatide treatment has been demonstrated to increase BMD of the lumbar vertebrae compared with denosumab, and reduces the risk of vertebral fracture, compared with bisphosphonates, for patients with corticosteroid induced osteoporosis.[200]​ Pre-clinical and animal trials suggest that abaloparatide may mitigate or prevent bone loss from glucocorticoids and improve fracture healing.[201]​ There are no available data on the evaluation of abaloparatide for the treatment of corticosteroid-induced osteoporosis from clinical trials.

Patients should be advised that stopping parathyroid hormone analogue treatment without transition to another therapy can result in bone loss. This can be prevented by starting oral or intravenous bisphosphonates for patients at low to moderate risk of fracture when the parathyroid hormone analogue and corticosteroids are discontinued.[87]​ If a fracture occurs when the patient has been treated with a parathyroid hormone analogue for ≥12 months, sequential therapy may include oral or intravenous bisphosphonates or denosumab.​[87]

If treated with denosumab sequential therapy, patients will require additional therapy with bisphosphonates 6-7 months after the last dose of denosumab to prevent rapid bone loss and development of new vertebral compression fractures.​[87]

Denosumab

Denosumab is approved for the management of glucocorticoid-induced osteoporosis in both men and women with a high risk of fracture, including those with a history of osteoporotic fractures, multiple clinical risk factors for fracture, and those who cannot tolerate or have not responded to other treatments (see the FDA warning in the information on denosumab in the postmenopausal women section).

The ACR recommends denosumab as a first-line option for adults with a moderate risk of fracture and adults aged ≥40 years at high risk of fracture.[87]​ ​​For adults aged ≥40 years at very high risk of fractures, denosumab is recommended as a second-line option.[87]​​

Denosumab should be used with caution in women of child bearing age due to potential adverse effects for the fetus, pregnancy should be avoided until 5 months after the last dose.[87]​ Denosumab treatment should be avoided when treating young adults with open growth plates.​

One systematic review reported that denosumab significantly increased BMD in the lumbar spine at 6 months, and in the lumbar spine and femoral neck at 12 months, compared with bisphosphonate therapy in patients with corticosteroid-induced osteoporosis.[202]

Patients with corticosteroid-induced osteoporosis treated with denosumab with a low to moderate risk of fracture when denosumab and corticosteroid therapy are stopped should receive 1-2 years of sequential therapy with a bisphosphonate to prevent rapid bone loss.​[87]​ ​If a new fracture occurs when the patients has been treated with denosumab ≥12 months, sequential therapy may include oral or intravenous bisphosphonates or romosozumab.​[87]

Romosozumab

Romosozumab is approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy, but has not been assessed for the treatment of corticosteroid-induced osteoporosis.[203]

However, the ACR conditionally recommends romosozumab as a treatment for adults aged ≥40 years at moderate to high risk of fracture, including those taking a high dose of corticosteroids (initial prednisolone dose ≥30 mg/day or cumulative prednisolone dose ≥5 g in 1 year) only if they are intolerant of all other treatments.[87]​ Romosozumab is not recommended for patients aged <40 years with a moderate to high risk of fracture, and should only be considered in those taking high-dose corticosteroids if other treatments are not tolerated.​[87]

Patients treated with romosozumab who are at a low or moderate risk of fracture when romosozumab and corticosteroid treatment is stopped will need sequential therapy with oral or intravenous bisphosphonate, for those who experience a new fracture after ≥12 months of romosozumab treatment, oral or intravenous bisphosphonate or denosumab can be used for sequential therapy.​[87]

Patients treated with denosumab for sequential therapy will require a further 6-7 months of bisphosphonate therapy to prevent rapid bone loss and the development of new vertebral compression fractures.​[87]

Raloxifene

Evidence on the effectiveness of raloxifene to treat patients with corticosteroid induced osteoporosis is lacking.[204]​ However, the ACR conditionally recommends raloxifene as a treatment for adults aged ≥40 years at moderate to high risk of fracture, including those taking a high dose of corticosteroids (initial prednisolone dose ≥30 mg/day or cumulative prednisolone dose ≥5 g in 1 year) only if they are intolerant of all other treatments.[87]​ Raloxifene is not recommended for patients aged <40 years with a moderate to high risk of fracture, and should only be considered in those taking high-dose corticosteroids if other treatments are not tolerated.​[87]

Patients treated with raloxifene who are at a low or moderate risk of fracture when raloxifene and corticosteroid treatment is stopped will not require sequential therapy.[87]​ If a new fracture occurs after treatment with raloxifene for ≥12 months, sequential therapy with oral or intravenous bisphosphonates is needed.​[87]

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