Section 6: Pharmacological treatment options

Recommendations

  1. Fracture risk assessment, patient suitability and preference and cost-effectiveness should inform the choice of drug treatment. In most people at risk of fragility fracture, anti-resorptive therapy is the first-line option (Strong recommendation).

Antiresorptive drug treatment

  1. Offer oral bisphosphonates (alendronate or risedronate) or intravenous zoledronate as the most cost-effective interventions. Alternative options include denosumab, ibandronate, hormone replacement therapy, raloxifene and strontium ranelate (Strong recommendation).
  2. Offer intravenous zoledronate as a first-line treatment option following a hip fracture (Strong recommendation).
  3. Consider offering younger postmenopausal women (age ≤ 60 years) with high fracture risk, and low baseline risk for adverse malignant and thromboembolic events, HRT as a first-line treatment option (Conditional recommendation).
  4. Discuss continued use of HRT after the age of 60 years with the patient, with treatment based on an individual risk-benefit analysis (Conditional recommendation).
  5. When HRT is discontinued, reassess fracture risk and consider an alternative treatment if indicated (Conditional recommendation).
  6. Before starting denosumab, ensure a long-term personalised osteoporosis management plan is in place and that both the patient and the primary care practitioner are made aware that denosumab treatment should not be stopped or delayed without discussion with a healthcare professional (Strong recommendation).
  7. Avoid unplanned cessation of denosumab because it can lead to increased vertebral fracture risk, hence it must not be stopped without considering an alternative therapy (Strong recommendation).
  8. If denosumab therapy is stopped, intravenous infusion of zoledronate is recommended 6 months after the last injection of denosumab, with subsequent monitoring of serum CTX guiding the timing of further treatment (Strong recommendation). Where monitoring of serum CTX is not possible, consider a further intravenous infusion of zoledronate 6 months after the first dose of zoledronate (Conditional recommendation).

Anabolic drug treatment

  1. Consider teriparatide, abaloparatide or romosozumab as first-line treatment options in postmenopausal women at very high fracture risk, particularly in those with vertebral fractures ( see Section 4) (Conditional recommendation).
  2. Consider teriparatide as a first-line treatment option in men age 50 years and older who are at very high fracture risk, particularly in those with vertebral fractures ( see Section 4) (Conditional recommendation).
  3. Consider as second-line treatment options, teriparatide in postmenopausal women, and men age 50 years and older, and abaloparatide or romosozumab in postmenopausal women, who are intolerant of bisphosphonate treatment, particularly in those with vertebral fractures (Conditional recommendation).
  4. Following the approved duration of treatment with teriparatide, abaloparatide or romosozumab (24, 18 or 12 months respectively), initiate treatment with alendronate, zoledronate or denosumab without delay (Strong recommendation).
  5. Consider raloxifene as an option for follow-on treatment after an anabolic drug in women (Conditional recommendation).

Other treatments

  1. When other antiresorptive and anabolic treatments are contraindicated or not tolerated, strontium ranelate can be used to treat postmenopausal osteoporosis and men with severe osteoporosis, provided the risk-benefit in relation to cardiovascular and thromboembolic events is considered. Initiation by a specialist who is an expert in osteoporosis management is advised (Strong recommendation).
  2. Offer calcium and/or vitamin D supplementation as an adjunct to anti-osteoporosis drug treatment, if dietary calcium is low and/or vitamin D insufficiency is a risk, respectively (Strong recommendation).
  3. Treat vitamin D deficiency and insufficiency prior to initiation of parenteral anti-osteoporosis drug treatment, and alongside initiation of oral anti-osteoporosis drug treatment (Strong recommendation).

Overview of treatment options

Drugs used in the management of osteoporosis can be considered under two broad headings based on their primary mode of action. Anti-resorptive drugs primarily inhibit osteoclastic bone resorption with later secondary effects on bone formation. Anabolic drugs primarily stimulate osteoblastic bone formation with variable effects on bone resorption. Most drugs fit into one or other category but romosozumab has a dual action, both stimulating bone formation and inhibiting bone resorption. Anti-resorptive drugs are much less expensive than anabolic drugs. It is important to consider the long-term management strategy for each patient initiated on osteoporosis treatment, as the timing of use of certain drugs is important, for example teriparatide can only be used once as a full course of treatment in a lifetime (abaloparatide and romosozumab do not have this restriction), whilst denosumab requires careful consideration before initiation given the difficulties in stopping treatment once it is started.

The drugs listed in table 6 have been shown to reduce fragility fractures in postmenopausal women, and men where indicated, with osteoporosis 187(Evidence levels Ia and Ib).

Table 6: Anti-fracture efficacy of approved drug treatments for postmenopausal women, and men, with osteoporosis when given with calcium and vitamin D
Evidence levels shown (see Appendix 3). HRT: hormone replacement therapy. NAE: No available evidence.
Intervention Vertebral fracture Non-Vertebral fracture Hip fracture Evidence of superiority or inferiority for vertebral fracture prevention in postmenopausal women with very high fracture risk Licenced for use in Men
Romosozumab Ib IIb IIb Superior to Alendronate (Ib) No
Teriparatide Ia Ia Ia Superior to Risedronate (Ib) Yes
Abaloparatide Ia Ia IIb NAE Yes
Alendronate Ia Ia Ia Inferior to Romosozumab (Ib) Yes
Ibandronate Ib Ib NAE NAE No
Risedronate Ia Ia Ia Inferior to Teriparatide (Ib) Yes
Zoledronate Ia Ia Ia NAE Yes
Calcitriol IIa NAE NAE NAE Yes
Denosumab Ia Ia Ia NAE Yes
HRT Ia Ia Ia NAE No
Raloxifene Ia NAE NAE NAE No
Strontium Ranelate Ia Ia IIb NAE Yes
  1. Vertebral Fractures

    The efficacy of the drugs listed in Table 6 is well established for the prevention of vertebral fractures. Teriparatide and romosozumab are superior to risedronate and alendronate respectively at reducing vertebral fractures in high-risk postmenopausal women with osteoporosis.

  2. Hip fractures

    Most drugs listed in Table 6 have been shown to reduce hip fracture incidence, with the exception of ibandronate, calcitriol, raloxifene and abaloparatide.

  3. Non-vertebral fractures

    Drugs listed in Table 6 (except calcitriol and raloxifene) have been shown to reduce the incidence of non-vertebral fractures.

  4. Drug initiation
    Primary and secondary care initiation

    Oral and intravenous bisphosphonates, denosumab, raloxifene, calcitriol, and HRT can be initiated by primary or secondary care clinicians. If denosumab is initiated in primary care, consultation with secondary care colleagues is advised given the need to have a long-term personalised osteoporosis management plan in place before denosumab is started, to enable denosumab, to be stopped in a managed way, as necessary. As calcitriol use is only supported by a grade IIa evidence base, its use is generally restricted to a select sub-group managed through secondary care. Strontium ranelate can be initiated by primary or secondary care clinicians, but if started in primary care should involve consultation with secondary care.

    Secondary care initiation

    Teriparatide, abaloparatide and romosozumab should be initiated by secondary care clinicians. In the UK teriparatide and romosozumab are provided via ‘home healthcare’ services, which also provide patient education.

    • Teriparatide and romosozumab have been shown to reduce hip fracture risk, whereas this has not been demonstrated for abaloparatide in the setting of a randomised controlled trial.
    • There is no consistent evidence from comparator studies to show superiority or otherwise of abaloparatide against anti-resorptives for any fracture type.
    • There is no evidence for superiority or otherwise of abaloparatide against teriparatide or romosozumab.
    • All three anabolic agents are approved for the treatment of osteoporosis in postmenopausal women at increased risk of fracture; however, only teriparatide is approved for use in men. NICE additionally recommends abaloparatide for people who identify as non-binary and trans men, registered female at birth, and romosozumab for people who are post-menopausal, not specifying sex.
    • Teriparatide is given for 24 months, abaloparatide for 18 months, and romosozumab for 12 months.
    • Teriparatide and abaloparatide are injected once daily, romosozumab is injected once monthly.
    • Teriparatide pens must be stored in the fridge. Unopened abaloparatide pens must be stored in the fridge before use; after opening they can be stored at room temperature for 30 days, after which they must be discarded.
    • Unlike teriparatide and abaloparatide which are single effect anabolic agents, romosozumab has a dual action conferring both anabolic and antiresorptive effects.
  6. Treatment sequence

    Any patient stopping denosumab, romosozumab, teriparatide or abaloparatide requires a sequential therapy strategy usually involving an anti-resorptive drug, which should be planned at the time the initial anabolic therapy is instigated to avoid a gap in treatment.

Specific drug options

Anti-resorptive drugs: Bisphosphonates

Alendronate 70mg once weekly by mouth is recommended for the treatment of women with postmenopausal osteoporosis (PMO), men with osteoporosis; glucocorticoid induced osteoporosis (GIO) and the prevention of PMO and GIO.

  1. The 70mg weekly dose is considered equivalent to the previously approved dose of 10mg daily.
  2. In postmenopausal women with osteoporosis, alendronate has been shown to reduce vertebral, non-vertebral and hip fractures 188;(Evidence level Ib). Approval for the use of alendronate in men with osteoporosis and in men and women taking glucocorticoids was granted on the basis of BMD bridging studies 189, 190;(Evidence level Ib). Although the daily dose of alendronate (10mgs) is licenced for use in men, this is considered equivalent to the weekly dose (70mg) which is commonly prescribed off-licence; (Evidence level IV).
  3. Common side-effects of alendronate include upper gastrointestinal symptoms, bowel disturbance, headaches and musculoskeletal pain.
  4. Alendronate should be taken after an overnight fast and at least 30 minutes before the first food or drink (other than water) of the day or any other oral medicinal products or supplementation (including calcium). Tablets should be swallowed whole with a glass of plain water (~200ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 30 minutes after taking the tablet. Alendronate is also available as 70mg effervescent or soluble tablets, to be dissolved in a glass of plain water (120ml).

Risedronate 35 mg once weekly by mouth is recommended for the treatment of PMO, men with osteoporosis; GIO and the prevention of GIO in women.

  1. The 35mg weekly dose is considered equivalent to the previously approved dose of 5mg daily.
  2. In postmenopausal women with osteoporosis, risedronate has been shown to reduce vertebral and non-vertebral fractures 191, 192; (Evidence level Ib). In a large population of older women, risedronate significantly decreased the risk of hip fractures, an effect that was greater in osteoporotic women 64; (Evidence level Ib). Approval for use of risedronate in men with osteoporosis and in postmenopausal women taking glucocorticoids was granted on the basis of BMD bridging studies 193-195 ; (Evidence levels Ib).
  3. Common side-effects include upper gastrointestinal symptoms, bowel disturbance, headache and musculoskeletal pain.
  4. Risedronate should be taken after an overnight fast and at least 30 minutes before the first food or drink (other than water) of the day or any other oral medicinal products or supplementation (including calcium). Tablets should be swallowed whole with a glass of plain water (120ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 30 minutes after taking the tablet.

Ibandronate 150mg once monthly by mouth or 3mg as a prefilled intravenous injection (usually given as a 15-30 second push via butterfly cannula) every 3 months is recommended for the treatment of postmenopausal women with osteoporosis.

  1. The 150mg monthly dose and 3mg 3-monthly intravenous dose are considered equivalent to the following doses: 2.5mg daily by mouth for the treatment of PMO.
  2. In postmenopausal women with osteoporosis, ibandronate 2.5mg daily has been shown to reduce vertebral fracture incidence 196; (Evidence level Ib). In a post-hoc analysis of women at high fracture risk (with a femoral neck BMD T-score below -3.0), a significant reduction in non-vertebral fractures was shown 197; (Evidence level Ib). No data are available to show efficacy of hip fracture risk reduction. Approval for the oral 150mg once monthly and 3mg intravenously every 3 months formulations was granted on the basis of BMD bridging studies 198,199; (Evidence levels Ib).
  3. Common side-effects with the oral preparation include upper gastrointestinal side-effects and bowel disturbance. Intravenous administration may be associated with an acute phase reaction, characterised by an influenza-like illness; this is generally short-lived and typically occurs only after the first injection.
  4. Oral ibandronate should be taken after an overnight fast and 1 hour before the first food or drink (other than water) of the day, or any other oral medicinal products or supplementation (including calcium). Tablets should be swallowed whole with a glass of plain water (180 to 240 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 1 hour after taking the tablet.

Zoledronate 5mg once yearly by intravenous infusion (as 5mg/100ml infusion given over a minimum of 15 minutes via an intravenous cannula) is recommended for the treatment of PMO, men with osteoporosis and men and postmenopausal women with GIO.

  1. In postmenopausal women with osteoporosis, zoledronate 5mg once yearly has been shown to reduce the incidence of vertebral, non-vertebral and hip fractures 200; (Evidence level Ib). Approval for use of zoledronate in men with osteoporosis and in men and women taking glucocorticoids was granted on the basis of BMD bridging studies 201, 202; (Evidence levels Ib).
  2. When given shortly after hip fracture, men and women given zoledronate 5mg annually had had fewer clinical fractures and lower mortality 3 years later 136; (Evidence level Ib).
  3. When given (without calcium supplementation) every 18 months to women with osteopenia, there were fewer vertebral and non-vertebral fractures 144203; (Evidence level Ib). A lower although non-significant decrease in mortality in fracture-free women, fewer breast cancers and fewer non-breast cancers were also reported as secondary outcomes by the end of the 6-year study.
  4. Common side-effects include an acute phase reaction usually only after the first infusion 204, which can be ameliorated by co-administration of paracetamol. Glomerular filtration rate (eGFR) should be calculated prior to initiation of treatment and caution advised for recipients at risk of kidney failure; monitoring for any increase in serum creatinine or reduction in eGFR. The MHRA recommends use of creatinine clearance instead of eGFR to inform treatment decisions in those age over 75 years and/or with BMI 40 kg/m2. An increase in symptomatic atrial fibrillation, reported as a serious adverse event, was seen in the main phase III trial 200; (Evidence level Ib).

Contraindications and special precautions for the use of bisphosphonates

  1. Oral and intravenous bisphosphonates are contraindicated in patients with hypocalcaemia, hypersensitivity to bisphosphonates, in women who are pregnant or lactating. Oral bisphosphonates are contraindicated in people with abnormalities of the oesophagus that delay oesophageal emptying such as stricture or achalasia, and inability to stand or sit upright for at least 30-60 minutes. They should be used with caution in patients with other upper gastrointestinal disorders.
  2. Zoledronate and risedronate are contraindicated in severe renal impairment (GFR ≤ 35 ml/min for zoledronate and ≤30 ml/min for risedronate), whilst alendronate and ibandronate are cautioned against (GFR ≤35 ml/min for alendronate and ≤ 30 ml/min for ibandronate).
  3. Pre-existing hypocalcaemia must be investigated and, where due to vitamin D deficiency, treated with vitamin D (e.g., 100,000 to 300,000 IU orally as a loading dose in divided doses) before zoledronate treatment is initiated.
  4. Rare adverse effects of long-term bisphosphonate treatment including osteonecrosis of the jaw and atypical femoral fractures are addressed in Section 7.

Anti-resorptive drugs: Denosumab

Denosumab is a fully humanised monoclonal antibody against Receptor Activator of Nuclear factor Kappa B Ligand (RANKL), a major regulator of osteoclast development and activity. It is approved for the treatment of PMO and men at increased fracture risk, for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased fracture risk (see Section 7), and for the treatment of bone loss associated with long term systemic glucocorticoid therapy in adults at risk of fragility fracture ( see Section 7) 205; (Evidence level Ib).

Denosumab is given as a subcutaneous injection of 60 mg once every 6 months. It has been shown to reduce the incidence of vertebral, non-vertebral and hip fractures in postmenopausal women with osteoporosis 206 and safety and efficacy are maintained over 10 years of treatment 207; (Evidence level Ib). Approval for its use in men with osteoporosis was granted on the basis of a BMD bridging study 208; (Evidence level Ib).

  1. Denosumab is contraindicated in patients with hypocalcaemia or with hypersensitivity to any of the constituents of the formulation. Its use is not recommended in pregnancy or in those age
  2. Hypocalcaemia, as a side-effect of denosumab treatment, increases with the degree of renal impairment; patients should be advised to report symptoms of hypocalcaemia. Pre-existing hypocalcaemia must be investigated and, where due to vitamin D deficiency, treated with vitamin D (e.g., 100,000 to 300,000 IU orally as a loading dose in divided doses) before denosumab treatment is initiated. Adequate intake of calcium and vitamin D is important in all patients, especially those with severe renal impairment.
  3. The SPC states all patients should have calcium checked prior to each dose. In patients predisposed to hypocalcaemia (e.g. patients with a creatinine clearance <35 ml/min), serum calcium levels should also be checked within two weeks after the initial dose 209.
  4. Side-effects include skin infection, predominantly cellulitis, eczema, hypocalcaemia, and flatulence. Rare adverse effects of denosumab include osteonecrosis of the jaw and atypical femoral fractures and are addressed in Section 7.
  5. Denosumab cessation leads to rapid reductions in BMD and elevations in bone turnover to levels above those seen before treatment initiation 210-212; (Evidence level Ib).
  6. Patients who discontinue denosumab have an increased risk of sustaining multiple vertebral fractures. In a post hoc analysis of the FREEDOM study and its extension, women discontinuing denosumab had an increased rate of vertebral fracture over an average of 3-6 months since the last denosumab injection was due. Of those patients who sustained vertebral fractures, 60.7% sustained multiple fractures compared to 38.7% of those discontinuing placebo 213, 214;(Evidence level Ib).
  7. The increase in vertebral fracture risk following cessation of denosumab therapy emphasises the need to continue treatment with an alternative anti-resorptive drug following denosumab withdrawal. An intravenous infusion of 5mg of zoledronate, 6 months after the last denosumab injection, reduces subsequent bone loss 215,219, although this effect is not seen in all patients and may not be maintained beyond one year, particularly in those who have had more than 3 years of denosumab treatment 220(Evidence levels IIa and IIb). Monitoring bone turnover markers at 3 and 6 months post zoledronate infusion can help guide timing of subsequent infusions. Where bone turnover markers are not available, a second infusion of zoledronate after 6 months has been proposed 221;(Evidence level IV). Oral alendronate 70 mg once weekly, was shown to maintain BMD for 12 months in most patients following one year of denosumab therapy, although significant bone loss occurred in a minority 222; (Evidence level IIa). Given the difficulties in stopping denosumab treatment, particularly careful consideration is needed before starting denosumab in younger postmenopausal women, and men.

Anti-resorptive drugs: Hormone replacement therapy (HRT)

HRT comprises a large number of oestrogen formulations or oestrogen plus progestogen combinations, some of which are approved for the prevention of osteoporosis in postmenopausal women at risk of fragility fracture. Conjugated equine oestrogens 0.625mg daily ± 2.5mg/day of medroxyprogesterone acetate has been shown to reduce vertebral, non-vertebral and hip fracture risk in postmenopausal women not selected on the basis of low bone density or high fracture risk 223, 224; (Evidence level Ib).

  1. The 2019 evidence review from NICE identified HRT was associated with lower fracture risk or increased BMD in nine out of 10 analyses, summarised from 2 cohort studies, one RCT, a Cochrane review and one other systematic review 225.
  2. The risk of venous thromboembolism (VTE) is increased by oral HRT compared with baseline population risk, but not with transdermal HRT (at standard doses) 225.
  3. HRT does not increase cardiovascular disease risk when started in women aged under 60 years 225.
  4. d. Systemic HRT is associated with an excess incidence of breast cancer, irrespective of the type of oestrogen or progestogen or route of delivery (oral or transdermal) 226.

Anti-resorptive drugs: Calcitriol

Calcitriol (1,25-dihydroxyvitamin D3) is the active form of vitamin D and, although rarely used now, is approved for the treatment of established postmenopausal osteoporosis in an oral dose of 0.25µg twice daily. It acts mainly by inhibiting bone resorption. It has been shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis but effects on non-vertebral and hip fractures have not been demonstrated 227; (Evidence level IIb). It is contraindicated in patients with hypercalcaemia or with metastatic calcification. Because calcitriol can cause hypercalcaemia and/or hypercalciuria, serum calcium and creatinine levels should be monitored at 1, 3 and 6 months after starting treatment and at 6 monthly intervals thereafter.

Anti-resorptive drugs: Raloxifene

Raloxifene is a selective oestrogen receptor modulator and inhibits bone resorption. It is approved for the treatment and prevention of osteoporosis in postmenopausal women. Raloxifene has been shown to reduce vertebral fracture risk but reduction in non-vertebral and hip fractures has not been demonstrated 228; (Evidence level Ib).

  1. Raloxifene is taken orally as a single daily 60mg dose and may be taken at any time without regard to meals.
  2. Raloxifene is contraindicated in women with child-bearing potential, unexplained uterine bleeding, severe hepatic or renal impairment and in women with a history of venous thromboembolism.
  3. Side-effects include leg cramps, oedema and vasomotor symptoms. There is a small increase in the risk of venous thromboembolism, mostly within the first few months of treatment and a small increase in the risk of fatal stroke has been reported 229, (Evidence level IIa) such that it should be used with caution in women with a history of stroke or with risk factors for stroke disease.
  4. In the phase III trials, women treated with raloxifene had a significantly decreased risk of developing breast cancer 230;(Evidence level Ib).

Other drugs: Strontium ranelate

Strontium ranelate is taken in a dose of 2g once at night by mouth as a suspension of granules stirred in water, at least two hours after food and/or consumption of calcium containing products. As an alkaline earth metal (closely related to calcium) it substitutes for calcium within hydroxyapatite. Its mode of action is not completely understood but the evidence suggests it has weak anti-resorptive effects whilst maintaining bone formation.

  1. In postmenopausal women with osteoporosis, strontium ranelate 2g daily has been shown to reduce the incidence of vertebral and non-vertebral fractures 231,232; (Evidence level Ib). Fewer hip fractures were reported in a post-hoc analysis of women at high risk of hip fracture (i.e., age ≥74 years with a femoral neck BMD T-score ≤-2.5)
  2. Approval for its use in men with osteoporosis was granted on the basis of a BMD bridging study 233; (Evidence level Ib).
  3. Common side effects include nausea and diarrhoea.
  4. There was a significant increase in venous thromboembolism in the Phase III trials 234.
  5. Contraindications include previous myocardial infarction, stroke, or venous thromboembolism as a post-hoc pooled safety analysis showed significant increases in myocardial infarction and “nervous system disorders” including cerebrovascular disease was observed in patients taking strontium ranelate compared to placebo 235.
  6. The manufacturer advises against use when the eGFR is
  7. The higher atomic number of strontium compared with calcium artefactually increases BMD when incorporated into the bone matrix 236. When strontium ranelate is stopped, this effect is slow to resolve with implications for future BMD monitoring.

Anabolic drugs: Teriparatide (recombinant human parathyroid hormone [PTH] 1-34)

When administered intermittently, teriparatide has anabolic skeletal effects which are most marked in trabecular bone. Teriparatide is approved for the treatment of osteoporosis in postmenopausal women and in men at risk of fragility fracture, and osteoporosis associated with systemic glucocorticoid therapy in women and men at risk of fragility fracture.

  1. Teriparatide is given as a subcutaneous injection in a dose of 20 µg/day. The duration of treatment is limited to 24 months.
  2. Teriparatide is contraindicated in patients with hypercalcaemia, metabolic bone diseases other than osteoporosis and osteogenesis imperfecta, severe renal impairment, malignant disease affecting the skeleton, prior radiation to the skeleton, and in women who are pregnant or lactating. Teriparatide should be used with caution in patients with moderate renal impairment.
  3. PTH levels need to be normal to initiate teriparatide, hence levels should be checked even with normocalcaemia.
  4. Side effects include headache, nausea, dizziness, postural hypotension and leg pain. Slight and transient elevations of serum calcium may occur following teriparatide injection.
  5. Teriparatide has been shown to reduce vertebral and non-vertebral fractures in postmenopausal women with osteoporosis 237; (Evidence level Ib). No primary efficacy end-point data are available for hip fracture incidence, but systematic review and meta-analysis level evidence has shown an OR for hip fracture risk of 0.44 (95% CI: 0.22, 0.87; p=0.019) in patients treated with teriparatide compared with placebo, when considering hip fracture as a safety end point. No significant benefit was seen on upper limb fractures 238; (Evidence level Ia). These findings were further supported by a network meta-analysis of a similar list of RCTs, which reported a HR of 0.35 (95% CI: 0.15, 0.73) for hip fracture in patients treated with teriparatide compared with placebo 239; (Evidence level Ia).
  6. Approval for teriparatide use in men with osteoporosis and in men and women with glucocorticoid-induced osteoporosis was granted on the basis of BMD bridging studies 240, 241; (Evidence level Ib).
  7. Teriparatide biosimilars are available which may improve the cost-effectiveness of generic teriparatide.

Anabolic drugs: Abaloparatide

Abaloparatide is a synthetic peptide analogue of the first 34 amino acids of the human parathyroid hormone-related peptide (PTHrP). It has anabolic skeletal effects and is approved for the treatment of osteoporosis in postmenopausal women at increased risk of fracture.

  1. Abaloparatide is given as a subcutaneous injection of 80 µg once daily. The duration of treatment is limited to 18 months.
  2. Abaloparatide is contraindicated in people with hypersensitivity to the active substance or to any of the excipients, pregnancy and breast-feeding, women of childbearing potential, pre-existing hypercalcaemia, severe renal impairment, unexplained elevations of serum alkaline phosphatase, patients with known risks for osteosarcoma such as those who have received prior external beam or implant radiation therapy involving the skeleton, and patients with skeletal malignancies or bone metastases.
  3. The European Medicines Agency SmPC specifies that patients should receive supplemental calcium and vitamin D if dietary intake is inadequate, and that no dosage adjustment is required in renal impairment; however, abaloparatide must not be used in people with severe renal impairment including patients with end-stage renal disease.
  4. Side-effects include hypercalcaemia and hypercalciuria, dizziness, back pain, nausea, headache, arthralgia, hypertension, injection site reaction, and palpitations.
  5. Abaloparatide has been shown to reduce vertebral fractures in postmenopausal women with osteoporosis. There was no statistically significant reduction in non-vertebral fractures (Evidence level 1b) 123. Two network meta-analyses have shown reduction in both vertebral and non-vertebral fractures when compared to placebo, with RRs for vertebral fracture of 0.14 (95% CI 0.05, 0.42) 242 and 0.13 (95% credible interval [CrI] 0.04, 0.34) 243, and RRs for non-vertebral fracture of 0.51 (95%CI 0.29,0.87) 242 and 0.50 (95% CrI 0.28, 0.85) 243(Evidence level Ia). A significant reduction in wrist fracture compared to placebo was also shown in one network meta-analysis (RR 0.39, 95% CrI 0.15, 0.90) 243(Evidence level Ia). There are insufficient data to assess efficacy against hip fracture. An analysis of real-world data in the US has suggested that abaloparatide is comparable to teriparatide for prevention of non-vertebral fractures, including hip fractures 244 ; (Evidence level IIb).

Anabolic drugs, with additional antiresorptive effect: Romosozumab

Romosozumab is a humanised monoclonal antibody that binds to and inhibits sclerostin. It has a dual action, stimulating bone formation and inhibiting bone resorption and is approved for the treatment of severe osteoporosis in postmenopausal women at very high risk of fracture. It is currently not approved for use in men. It is given as a subcutaneous injection in a dose of 210 mg (administered as two subcutaneous injections of 105mg each) once monthly. The duration of treatment is limited to 12 months.

  1. In postmenopausal women with osteoporosis who received romosozumab 210mg or placebo subcutaneously once monthly for 12 months followed by denosumab 60mg subcutaneously in both groups for 12 months, new vertebral fractures and clinical fractures were significantly reduced in women treated with romosozumab when compared to placebo at 12 months, and at 24 months vertebral fracture rates were significantly lower in women treated with romosozumab during the first 12 months 120; (Evidence level Ib).
  2. In a comparator-controlled study in postmenopausal women with severe osteoporosis subcutaneous romosozumab 210mg once monthly for 12 months followed by oral alendronate 70mg once weekly for 12 months was compared against alendronate 70mg once weekly for 24 months) 121. New vertebral, non-vertebral, clinical and hip fractures were all significantly lower in women treated with romosozumab followed by alendronate than in those treated with alendronate alone (Evidence level Ib). Significantly greater risk reduction in new vertebral and clinical fractures was seen for romosozumab vs. alendronate at 12 months. A significantly higher incidence of cardiovascular events was seen in the romosozumab group compared to the alendronate group 120; (Evidence level Ib).
  3. Romosozumab is contraindicated in patients with hypocalcaemia, hypersensitivity to any of the constituents of the formulation, or a history of myocardial infarction or stroke.
  4. When determining whether to use romosozumab for an individual patient, both fracture and cardiovascular risk (based on risk factors) over the next year need to be considered.
  5. Transient hypocalcaemia has been observed in patients receiving romosozumab. Hypocalcaemia should be corrected prior to initiation of treatment and patients should be adequately supplemented with calcium and vitamin D. Patients with severe renal impairment or on dialysis are at increased risk of developing hypocalcaemia. Osteonecrosis of the jaw and atypical femoral fractures have been very rarely reported with romosozumab use.

Drug treatment for patients with very high fracture risk

Evidence Summary

  1. Two randomised comparator-controlled studies in postmenopausal women with severe osteoporosis have demonstrated superior anti-fracture efficacy of skeletal anabolic agents versus anti-resorptive drugs. Subcutaneous romosozumab 210 mg once monthly resulted in significantly greater reduction of vertebral, non-vertebral, clinical and hip fractures at 24 months (risk reduction of 48%, 19%, 27% and 38% respectively) and significantly greater risk reduction in new vertebral and clinical fractures at 12 months when compared to oral alendronate 70 mg once weekly. In the VERtebral fracture treatment comparisons in Osteoporotic women (VERO) study, subcutaneous teriparatide, 20 µg once daily, was associated with significantly fewer new vertebral and clinical fractures than oral risedronate, 35mg once weekly (56% and 52% respectively) after 2 years of treatment 245; (Evidence level Ib). These studies provide the rationale for considering teriparatide or romosozumab as a first-line treatment option in postmenopausal women at very high risk of fracture (see Section 4). Comparator studies of anti-resorptive and anabolic agents have not been reported in men.
  2. Following discontinuation of treatment with teriparatide or romosozumab, bone turnover increases and there is a fall in BMD. Although not specifically studied for abaloparatide, similar changes would be expected. Since the maximum permitted duration of treatment with teriparatide is 24 months, with abaloparatide 18 months, with romosozumab 12 months, sequential therapy with anti-resorptive drugs is required to maintain their beneficial skeletal effects.
  3. Both alendronate and denosumab have been shown to maintain and increase BMD at the spine and hip following teriparatide or romosozumab therapy 121,246-249 . In the FRAME extension study, the beneficial effects of 12 months romosozumab therapy on vertebral and non-vertebral fracture risk were maintained when followed by 24 months of denosumab treatment 250;(Evidence level IIb). Sequential therapy with alendronate following 18 months treatment with abaloparatide results in further gains in BMD and sustained reductions in vertebral and non-vertebral fracture rates 251; (Evidence level IIb).
  4. When women are switched from oral bisphosphonates to teriparatide or romosozumab, there is attenuation of the increase in spine and hip BMD compared to when these agents are used in treatment-naïve individuals. This blunting effect is greater for teriparatide than romosozumab, especially at the hip 252, 253; (Evidence level IIb). The impact of these effects, if any, on fracture risk is unknown. The effect of switching from oral bisphosphonates to abaloparatide on the efficacy or effectiveness of abaloparatide treatment is unknown.
  5. In women previously treated with denosumab, switching to teriparatide is associated with transient bone loss in the spine and greater and longer lasting bone loss in the hip 247. When romosozumab is given following denosumab therapy, there is attenuation of the BMD increase at the spine and hip 245,254 ; (Evidence level IIb). The impact of these effects, if any, on fracture risk is unknown.