Osteoporosis update 2013

Cooper, C. Cooper, R. Francis, J. Kanis, D. Marsh, E. McCloskey, D. Reid, P. Selby, M. Rheumatoid arthritis. There are many secondary causes of osteoporosis e.

By contrast, rheumatoid arthritis increases fracture risk independently of BMD and the use of glucocorticoids [ 37 ] Evidence level 1a. Recent information suggests that diabetes particularly type 2 may also exert BMD-independent effects on fracture risk [ 39 , 40 ]. The consideration of these risk factors improves the sensitivity of testing without sacrificing specificity, and the writing group recommend their inclusion in case-finding algorithms Grade B recommendation.

Indeed, the use of combined clinical risk factors alone performs very similarly to that of BMD alone [ 41 ]; the use of clinical risk factors with the addition of BMD is optimal, but the latter can be included in targeted groups see below. There are many additional risk factors for fracture that act solely by reducing BMD and others that have been less well validated or identify a risk that may not be amenable to particular treatments.

Liability to falls is an appropriate example where the risk of fracture is high, but treatment with agents affecting bone metabolism have an uncertain effect on fracture risk in such patients. The writing group recommend the identification and validation of additional clinical risk factors as an important area for further research. Biochemical indices of skeletal turnover have the potential to aid risk assessment but probably play a more immediate role in the monitoring of treatment [ 42 ] Evidence level Ia.

Further research in this field is recommended so that their utility in clinical practice can be evaluated for use in diagnosis, prognosis and monitoring of treatment [ 43 ]. The International Osteoporosis Foundation recommends that risk of fracture should be expressed as an absolute risk, i. The absolute risk of fracture depends upon age and life expectancy as well as the current relative risk. The period of 10 years covers the likely initial duration of treatment and the benefits that may continue if treatment is stopped.

The FRAX tool www. A major osteoporotic fracture is a clinical spine, hip, forearm or humerus fracture. The tool has been externally validated in independent cohorts [ 30 ] Evidence level Ia. The National Institute for Health and Care Excellence NICE has recommended the use of fracture risk assessment tools FRAX or QFracture in the assessment of patients, including the proposal that their use should be considered in all women age 65 years or older and men age 75 years or older [ 29 ].

Since FRAX and QFracture yield different outputs probability of fracture accounting for mortality risk in the case of FRAX, and a cumulative risk of fracture in the case of QFracture , the two calculators cannot be used interchangeably. The FRAX assessment takes no account of prior treatment or of dose responses for several risk factors.

For example, two prior fractures carry a much higher risk than a single prior fracture. Dose responses are also evident for glucocorticoid use and are partially addressed in the NOGG guideline.

A prior clinical vertebral fracture carries an approximately 2-fold higher risk than other prior fractures. Since it is not possible to model all such scenarios with the FRAX algorithm, these limitations should temper clinical judgement.

Diagnostic assessment of individuals with osteoporosis should include not only the assessment of BMD where indicated but also the exclusion of diseases that mimic osteoporosis, elucidation of the cause of the osteoporosis and the management of any associated morbidity.

Recommendations for the routine investigation of patients with osteoporosis are shown in Table 1. The majority of vertebral fractures do not come to medical attention and thus remain undiagnosed [ 47 ].

Moderate or severe vertebral fractures, even when asymptomatic, are strong risk factors for subsequent fracture at the spine and other skeletal sites [ 48 — 50 ]. Vertebral fracture assessment should therefore be considered in high-risk individuals, using either lateral lumbar and thoracic spine radiographs or lateral spine DXA imaging. The latter delivers a significantly lower radiation dose but performs comparably to traditional radiographs [ 51 ].

It should also be considered in individuals with a history of non-vertebral fracture after the age of 50 years [ 52 ]. Increasing calcium intake, either through the diet or in the form of supplements, has been shown to result in small increases in BMD [ 53 ] Evidence level 1a but convincing evidence that calcium alone reduces fracture risk is lacking [ 54 , 55 ] Evidence level 1a.

Calcium supplements are associated with an increased risk of nephrolithiasis [ 56 ] and gastrointestinal side-effects. Concerns have also been raised that calcium supplements increase the risk of cardiovascular disease, but in a recent meta-analysis little evidence was found for a significant association [ 57 ] Evidence level 1a. However, in postmenopausal women and older men at increased risk of fracture, the available evidence supports the use of higher doses.

Vitamin D alone is ineffective in reducing fracture risk but when combined with calcium supplements results in a small reduction in hip and non-vertebral fractures, and possibly also in vertebral fractures [ 59 , 60 ] Evidence level 1a. This dose of vitamin D may also reduce falls [ 62 ] Evidence level 1a.

Intermittent administration of large doses of vitamin D, e. Supplementation with calcium and vitamin D is often advocated as an adjunct to other treatments for osteoporosis, as the clinical trials of these agents were performed in patients who were calcium and vitamin D replete. Weight-bearing exercise has beneficial effects on BMD [ 65 ] Evidence level 1a but has not been shown to reduce fracture risk [ 66 ] Evidence level 1a.

Regular weight-bearing exercise should be advised, tailored according to the individual patient Grade B recommendation. Physiotherapy is an important component of rehabilitation after fracture. Muscle strengthening and balance training exercise interventions may reduce falls by improving confidence and coordination as well as maintaining bone mass.

The majority of fractures are preceded by a fall. Multi-component group and home-based exercise programmes, Tai Chi and home safety interventions have been shown to reduce the risk of falls in people living in the community [ 67 ] Evidence level 1a. Falls history should be obtained in patients with osteoporosis and further assessment and appropriate measures undertaken in those at risk Grade B recommendation. Hip protectors may reduce the risk of hip fractures in older people in nursing care or residential care settings [ 69 ] Evidence level 1a.

However, poor acceptance and adherence by older people offered hip protectors are barriers to their use. Sufficient protein intake is necessary to maintain the function of the musculoskeletal system and also decreases the complications that occur after hip fracture.

Protein supplementation in patients with a recent hip fracture has been shown to improve the subsequent clinical course by significantly lowering the rate of infection and duration of hospital stay [ 70 ] Evidence level Ib.

In the context of strategies for treating individuals at high risk of fracture, no distinction is made between prevention and treatment. A range of pharmacological interventions has been shown to be effective in reducing fracture risk in postmenopausal women with osteoporosis [ 71 ]. Recommendations concerning the major interventions for osteoporosis are based on high levels of evidence Evidence level 1a and Ib , and the grade of these recommendations is summarised in Table 2.

Alendronate is approved for the treatment of postmenopausal osteoporosis 10 mg daily or 70 mg once weekly by mouth and osteoporosis in men 10 mg daily.

It is also approved for the prevention of postmenopausal osteoporosis 5 mg daily and for prevention and treatment of glucocorticoid-induced osteoporosis 5 mg daily or, in postmenopausal women not receiving hormone replacement therapy 10 mg daily. In postmenopausal women with osteoporosis, alendronate at 10 mg daily has been shown to reduce vertebral, non-vertebral and hip fractures [ 72 ].

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 [ 73 , 74 ]. Side-effects include upper gastrointestinal symptoms, bowel disturbance, headaches and musculoskeletal pain. Alendronate should be taken after an overnight fast and at least 30 min before the first food or drink other than water of the day or any other oral medicinal products or supplementation including calcium.

Patients should not lie down for 30 min after taking the tablet. Ibandronate at mg once monthly by mouth or 3 mg as an intravenous injection every 3 months is approved for the treatment of osteoporosis in postmenopausal women at increased risk of fracture. In a dose of 2. No data are available for hip fracture. Approval for the oral mg once monthly and 3 mg intravenously every 3-month formulations was granted on the basis of BMD bridging studies. 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. Oral ibandronate should be taken after an overnight fast and 1 h 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 to ml while the patient is sitting or standing in an upright position.

Patients should not lie down for 1 h after taking the tablet. Risedronate at 5 mg daily or 35 mg once weekly by mouth is approved for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fracture and for the treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. It is also indicated for the treatment of osteoporosis in men at high risk of fractures.

Risedronate at 5 mg daily is approved for the prevention of glucocorticoid-induced osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, risedronate at 5 mg daily has been shown to reduce vertebral and non-vertebral fractures [ 77 , 78 ]. In a large population of older women, risedronate significantly decreased the risk of hip fractures, an effect that was greater in osteoporotic women [ 79 ].

Approval for use of risedronate in men with osteoporosis and in postmenopausal women taking glucocorticoids was granted on the basis of BMD bridging studies [ 80 — 82 ]. Side-effects include upper gastrointestinal symptoms, bowel disturbance, headache and musculoskeletal pain. Risedronate should be taken after an overnight fast and at least 30 min before the first food or drink other than water of the day or any other oral medicinal products or supplementation including calcium.

Zoledronic acid at 5 mg intravenously once yearly is approved for the treatment of osteoporosis in postmenopausal women and men at increased risk of fracture, including those with a recent low trauma fracture, and for the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in postmenopausal women and men.

Zoledronic acid has been shown to reduce the incidence of vertebral, non-vertebral and hip fractures in postmenopausal women with osteoporosis [ 83 ] and to reduce the risk of clinical fracture and attendant mortality when given to patients shortly after their first hip fracture [ 84 ].

Approval for its use in men with osteoporosis and postmenopausal women and men taking glucocorticoids was granted on the basis of BMD bridging studies [ 85 , 86 ]. Side-effects include an acute phase reaction see above , usually only after the first infusion, and gastrointestinal symptoms.

Creatinine clearance should be calculated e. An increase in atrial fibrillation, reported as a serious adverse event, was seen in the main phase III trial although this finding has not been replicated in other trials involving zoledronic acid. Zoledronic acid is given as an intravenous infusion over a minimum period of 15 min. Pregnancy and lactation are also contraindications. 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 min.

They should be used with caution in patients with other upper gastrointestinal disorders. Pre-existing hypocalcaemia must be investigated and, where due to vitamin D deficiency, treated with vitamin D e.

Rare adverse effects, in particular, osteonecrosis of the jaw and atypical femoral fractures, have led to additional precautions. In patients with dental disease or other risk factors e. While on treatment, patients should avoid invasive dental procedures if possible.

For patients requiring dental procedures, there are no data available to indicate whether discontinuation of treatment reduces the risk of osteonecrosis of the jaw. During treatment, all patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and report any oral symptoms such as dental mobility, pain or swelling.

The possibility of osteonecrosis of the external auditory canal should be considered in patients who present with ear symptoms including chronic ear infections. During treatment, patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for possible atypical femur fracture.

It is approved for the treatment of osteoporosis in postmenopausal women and men at increased risk of fractures, and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. It is given as a subcutaneous injection of 60 mg once every 6 months. Denosumab has been shown to reduce the incidence of vertebral, non-vertebral and hip fractures in postmenopausal women with osteoporosis [ 87 ]. Approval for its use in men with osteoporosis was granted on the basis of a BMD bridging study [ 88 ].

Denosumab is contraindicated in women with hypocalcaemia or with hypersensitivity to any of the constituents of the formulation. Side-effects include skin infection, predominantly cellulitis, and hypocalcaemia. Hypocalcaemia is an identified risk in patients treated with denosumab, which increases with the degree of renal impairment. Adequate intake of calcium and vitamin D is important in all patients, especially in those with severe renal impairment.

Monitoring of calcium levels should be conducted prior to each dose of denosumab and within 2 weeks after the initial dose in patients predisposed to hypocalcaemia e. Patients should be advised to report symptoms of hypocalcaemia. The rare occurrence of osteonecrosis of the jaw and atypical femoral fractures in patients treated with denosumab has led to additional precautions.

During treatment, patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an atypical femur fracture. Following cessation of denosumab therapy, rapid bone loss occurs [ 89 ]. Whether this results in an increase in fracture risk is unclear, but there are case reports of vertebral fractures, often multiple, occurring within 18 months after stopping treatment [ 90 — 92 ].

Although further studies are required, in patients who stop denosumab, switching to an alternative therapy such as a bisphosphonate should be considered Grade C recommendation. 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 [ 93 ].

Raloxifene is contraindicated in women with child-bearing potential, a history of venous thromboembolism or unexplained uterine bleeding. Hepatic impairment and severe renal impairment are also contraindications. It should be used with caution in women with a history of stroke or with risk factors for stroke.

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. In the phase III trials, women treated with raloxifene had a significantly decreased risk of developing breast cancer.

Raloxifene is taken orally as a single daily dose 60 mg and may be taken at any time without regard to meals. Teriparatide recombinant human parathyroid hormone PTH 1—34 , when administered intermittently, has anabolic skeletal effects which are most marked in cancellous bone.

Teriparatide is approved for treatment of osteoporosis in postmenopausal women and in men at high risk of fracture. Teriparatide is also approved for the treatment of osteoporosis associated with systemic glucocorticoid therapy in women and men at increased risk of fracture.

Teriparatide has been shown to reduce vertebral and non-vertebral fractures in postmenopausal women with osteoporosis [ 97 ]. No data are available for hip fractures.

Approval for its use in men with osteoporosis and in glucocorticoid-induced osteoporosis was granted on the basis of BMD bridging studies [ 98 , 99 ]. Teriparatide is contraindicated in patients with hypercalcaemia, pregnancy and lactation, metabolic bone diseases other than osteoporosis, severe renal impairment, prior radiation to the skeleton and malignant disease affecting the skeleton.

It should be used with caution in patients with moderate renal impairment. Side-effects include headache, nausea, dizziness and postural hypotension. Slight and transient elevations of serum calcium may occur following teriparatide injection. The duration of treatment is limited to 24 months.

Calcitriol 1,dihydroxyvitamin D is the active form of vitamin D and is approved for the treatment of established postmenopausal osteoporosis in an oral dose of 0. 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 [ ]. It is contraindicated in patients with hypercalcaemia or with metastatic calcification.

Hormone replacement therapy HRT comprises a large number of formulations of oestrogen or oestrogen plus progestogen combinations, some of which are approved for the prevention of osteoporosis in postmenopausal women at high risk of fracture.

Conjugated equine oestrogens 0. No trials have been designed and powered to detect differences in the magnitude of fracture reduction between different treatments. The choice of agent is determined by the spectrum of anti-fracture effects across skeletal sites, side-effects and cost. The low cost of generic formulations of alendronate and risedronate, which have a broad spectrum of anti-fracture efficacy, make these first line treatments in the majority of cases.

In women who are intolerant of oral bisphosphonates or in whom they are contraindicated, intravenous bisphosphonates or denosumab provide appropriate and cost-effective treatment options with hormone replacement therapy or raloxifene as additional options Grade A recommendation. The high cost of teriparatide restricts its use to those at very high risk, particularly for vertebral fractures.

Concerns over rare adverse effects of long-term bisphosphonate therapy, particularly osteonecrosis of the jaw and atypical femoral fractures, have raised questions about the optimal duration of therapy. Because bisphosphonates are retained in bone for varying periods of time, beneficial effects may persist for some time after cessation of treatment. This has led to the suggestion that some patients may benefit from a period off treatment, in which treatment is stopped after some years and the need for continued therapy is subsequently reassessed.

Treatment review in patients taking bisphosphonates is therefore important [ ]. Because pivotal clinical trials have mostly been limited to a duration of 3 years, recommendations for longer-term use and for drug holidays are based on limited evidence from extension studies in postmenopausal women [ ]. There is currently no evidence on which to base recommendations for men. Withdrawal of treatment is associated with decreases in BMD and increased bone turnover after 2—3 years for alendronate [ , ] and 1—2 years for ibandronate and risedronate [ , ].

In the Fracture Intervention Trial Long-term Extension study of alendronate FLEX , there were significantly fewer clinical vertebral fractures in women previously treated with alendronate for 5 years who continued with alendronate for five more years than in those assigned to placebo after 5 years of alendronate [ ].

In the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly HORIZON study extension, the risk of morphometric vertebral fractures was significantly lower in women continuing on zoledronic acid for 3 years after 3 years therapy when compared with those switched to placebo, but the risk of non-vertebral fractures was similar in the treatment and placebo groups [ ].

Older age was also associated with increased fracture risk after discontinuation of alendronate therapy [ ]. Based on the evidence above, continuation of bisphosphonate treatment beyond 3—5 years 3 years for zoledronic acid and 5 years for alendronate, ibandronate and risedronate can generally be recommended in the following situations: Evidence level IIb, Grade of recommendation B. Treatment review should be performed after 5 years of treatment with alendronate, risedronate or ibandronate and after 3 years of treatment with zoledronic acid Grade C recommendation.

The NOGG intervention thresholds can then be used to guide the decision as to whether treatment can be stopped for a period of time Fig. An algorithm outlining the above approach is shown in Fig. If biochemical markers of bone turnover indicate relapse from suppressed bone turnover and BMD has decreased following withdrawal, resumption of treatment should be considered Grade C recommendation. There is no evidence base to guide decisions about treatment beyond 10 years and management of such patients should be considered on an individual basis.

Osteonecrosis of the jaw occurs only very rarely in patients receiving bisphosphonate or denosumab therapy for osteoporosis. Risk factors for osteonecrosis of the jaw include poor oral hygiene, dental disease, dental interventions, cancer, chemotherapy or glucocorticoid therapy [ ]. The incidence of osteonecrosis of the jaw is substantially greater with the higher doses of bisphosphonates or denosumab that are used to treat patients with skeletal metastases. Atypical femoral fractures , mainly of the subtrochanteric and diaphyseal regions of the femoral shaft, have been reported rarely in patients taking bisphosphonates or denosumab for osteoporosis.

In a recent review by the ASBMR Task Force on the management of osteoporosis in patients on long-term bisphosphonates, a systematic search of the literature revealed wide variation in the relative risk of atypical femoral fractures associated with BP use between 2- and fold , but the absolute risk was consistently low, ranging between 3. A typical femoral fractures are often bilateral, associated with prodromal pain and tend to heal poorly. During bisphosphonate or denosumab therapy, patients should be advised to report any unexplained thigh, groin or hip pain and if such symptoms develop, imaging of the femur X-ray, isotope scanning or MRI should be performed.

If an atypical fracture is present, the contralateral femur should also be imaged. Discontinuation of bisphosphonate or denosumab therapy should be considered in patients who develop an atypical fracture, weight-bearing activity should be restricted and alternative treatment options considered where appropriate. Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer.

In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Osteoporosis is a metabolic bone disorder characterized by progressive decline of bone mass and bone quality, leading to bone fragility and an increased risk of fracture.

Osteoporosis occurs when bone resorption outpaces bone formation during bone remodelling. Research 10 January Open Access. Mechanical force is critical for the development and remodeling of bones. Here the authors report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine via regulating the expression of the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 in osteoblasts. Research 14 December Open Access.

Research 15 November Open Access.