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Recent Management Controversies in Osteoporosis levels are above 30 ng/ml,13 and studies of optimal levels of 25(OH)D for

maximising intestinal calcium absorption have demonstrated that optimal calcium absorption occurs with 25(OH)D levels >32 ng/ml.15

The IOM’s recommended upper limit of 50 ng/ml for serum 25(OH)D was supported by a randomised, placebo-controlled trial in elderly women that evaluated the effect of high dose vitamin D on falls and fractures. In this trial, women were randomised to cholecalciferol 500,000 IU/year or placebo for 3–5 years. The study found a statistically significant increase in both falls and fractures in the group treated with vitamin D. Interestingly, a post hoc analysis demonstrated that the risk of falls and fractures was exacerbated in the first three months after vitamin D dosing when 25(OH)D levels exceeded 48 ng/ml.16

The large yearly dose that was used in this

study is not currently used in the US, therefore the fall risk demonstrated in this study is not applicable to US patients undergoing vitamin D therapy. In contrast to this study, a meta- analysis was performed to evaluate the effect of vitamin D on fall prevention. This meta-analysis included eight randomised controlled trials, in which the mean dose of cholecalciferol was 700–1,000 IU/day. The authors found that vitamin D supplementation decreased the risk of falling by 19 %, and patients who reached 25(OH)D levels of 60 ng/ml experienced 23 % fewer falls.17


these data, the AACE recommends using vitamin D supplementation to maintain 25(OH)D levels of 30–60 ng/ml.1

Duration of Pharmacologic Therapy Pharmacologic therapy is recommended for patients with a history of hip or spine fracture and a BMD of 2.5 SDs below the young adult mean (as measured by dual-energy X-ray absorptiometry [DXA]), as well as for patients with a high probability of fractures as determined using the FRAX® tool. The FRAX tool was developed by the WHO to determine the 10-year risk of fracture ( It considers multiple factors, including previous fracture, BMD, body mass index (BMI), secondary causes of osteoporosis, and family history. Patients should be considered for treatment if the 10-year risk of hip fracture is greater than 3 % or if the 10-year risk of major osteoporotic fracture is greater than 20 %.1

Pharmacologic therapy should be initiated with a first-line agent such as alendronate, risedronate, zoledronic acid, or denosumab. These agents have been shown to decrease the risk of hip and non-vertebral fractures in randomised, prospective trials.1

The majority of first-line

agents are bisphosphonates, which are the most widely used drugs for treatment of osteoporosis. However, recent studies have questioned the long-term treatment of osteoporosis with bisphosphonates due to an association with atypical fractures. In particular, alendronate has been associated with subtrochanteric fracture.18

Several case series have been reported that demonstrate a possible relationship between long-term bisphosphonate therapy and atypical subtrochanteric fractures. The earliest series to be published demonstrated that a small number of patients had low energy non-vertebral fractures while on alendronate. Bone biopsies in these patients revealed severely suppressed bone turnover,18

therefore it

was postulated that, since bisphosphonates reduce bone remodeling, they might lead to ‘frozen’ bone or over-suppressed bone that is susceptible to stress fractures. These atypical fractures have been defined by a task force of the American Society for Bone and Mineral Research (ASBMR) (see Table 4).19

EUROPEAN ENDOCRINOLOGY Table 4: Features of Atypical Femoral Fracture19

Major Features • Located along the femur, most commonly proximal one-third • Associated with little trauma, fall from standing height or less • Transverse or oblique configuration • Non-comminuted • Complete fractures extend through both cortices and may be associated with medial spike; incomplete fractures only involve lateral cortex

Minor Features • Localised periosteal reaction of lateral cortex • Generalised increase in cortical thickness of diaphysis • Prodromal symptoms, dull or aching pain • Bilateral fractures • Delayed healing • Comorbid conditions (vitamin D deficiency, hypophosphatasia) • Use of pharmaceutical agents (BPs, PPIs, GCs)

BPs = bisphosphonates; GCs = glucocorticoids; PPIs = proton pump inhibitors. Source: Shane, et al., 2010.19

Since the publication of these initial case series involving atypical fractures, several larger studies have reviewed data on such fractures. A registry-based, cross-sectional study did not find an increased incidence of fractures in patients receiving alendronate.20

In addition, a

secondary analysis was performed of three large, randomised bisphosphonate trials – the Fracture intervention trial (FIT), the FIT long-term extension (FLEX) trial and the Health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial (HORIZON PFT). A total of 14,195 women were enrolled in these studies and 134 hip or femur fractures qualified for inclusion in the analysis. Of these fractures, 12 occurred in the subtrochanteric or diaphyseal femur, equivalent to a fracture rate of 2.3 per 10,000 patient-years. This represents an extremely low risk for atypical fractures even in patients who received alendronate therapy for 10 years.21

A Swedish population-based case-control study analysed all femoral subtrochanteric and shaft fractures that occurred in one year. This study identified 59 patients with atypical fractures, of which 46 occured in patients on bisphosphonate therapy, equivalent to an absolute risk of 0.0005 or an incidence of five per 10,000 patient years.22

This supports the findings of low incidence rates for atypical fractures in the randomised bisphosphonate trials, and confirms that the absolute risk of atypical fractures is small compared with the high risk of osteoporotic fractures if patients are not treated. In addition, the task force of the ASBMR did not find any data to support a causal relationship between bisphosphonate therapy and atypical fractures.19

The Swedish population-based study did demonstrate an increased risk of atypical fracture with duration of bisphosphonate use (odds ratio 1.3 per 100 prescribed daily doses),22

indicating that it is

reasonable to limit the duration of bisphosphonate therapy. The task force of the ASBMR reviewed the literature and found that atypical fractures occur after a median length of treatment with bisphosphonates of seven years. The task force recommends continuing therapy for five years and then determining the need for further therapy on a yearly basis according to the clinical scenario. It is reasonable to consider a holiday from bisphosphonates after five years of treatment, but currently there are no data indicating a decrease in atypical fractures for these patients.20


recommends considering a one- to two-year drug holiday after four to five years of treatment with alendronate in patients with mild


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