Section 6: Pharmacological treatment options

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 and raloxifene.

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.

   Primary and secondary care initiation
   

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

5. Treatment sequence

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

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.

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 ^{182, 183}; (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 ^184-186 ; (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 ¹⁸⁷; (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 ¹⁸⁸; (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 ^189,190; (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 ¹⁹¹; (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 ^{192, 193}; (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 ¹³⁰; (Evidence level Ib).
3. When given (without calcium supplementation) every 18 months to women with osteopenia, there were fewer vertebral and non-vertebral fractures ¹³⁸¹⁹⁴; (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 ¹⁹⁵, 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 ¹⁹¹191; (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.

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) ¹⁹⁶; (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 ¹⁹⁷ and safety and efficacy are maintained over 10 years of treatment ¹⁹⁸; (Evidence level Ib). Approval for its use in men with osteoporosis was granted on the basis of a BMD bridging study ¹⁹⁹; (Evidence level Ib).

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 ^{214, 215}; (Evidence level Ib).

Calcitriol (1,25-dihydroxyvitamin D3) is the active form of vitamin D and 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 ²¹⁸218; (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.

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 ²¹⁹; (Evidence level Ib).

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.

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. 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 ²³³; (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 either teriparatide or romosozumab, bone turnover increases and there is a fall in BMD. Since the maximum permitted duration of treatment with teriparatide is 24 months and 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 either teriparatide or romosozumab therapy ^116,234-237 . 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 ²³⁸;(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 ^{239, 240}; (Evidence level IIb). The impact of these effects, if any, on fracture risk 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 ²³⁵. When romosozumab is given following denosumab therapy, there is attenuation of the BMD increase at the spine and hip ^233,241 ; (Evidence level IIb). The impact of these effects, if any, on fracture risk is unknown.