Progress in Osteoporosis and Fracture Prevention: Focus on Postmenopausal Women

Kenneth G Saag; Piet Geusens


Arthritis Res Ther. 2009;11(5):251 

In This Article

Differential Diagnosis in Patients with Osteoporosis or a Fragility Fracture or Both

Randomized controlled trials on fracture prevention in postmenopausal women exclude patients with secondary osteoporosis, except in studies in glucocorticoid users. However, patients with BMD-diagnosed osteoporosis or presenting with a clinical fracture or both often have contributors to secondary osteoporosis. FRAX includes a long list of causes of secondary osteoporosis that contribute to fracture risk independently of other clinical risks and BMD (Table 1).[2,3] Differential diagnosis in the context of case finding therefore includes a thorough medical history and clinical examination. Based on FRAX, laboratory investigations can contribute to case finding, but FRAX does not give instructions on how to exclude other contributors to secondary osteoporosis that are frequently found in patients with osteoporosis or fractures or both.[21,22] In patients with BMD-based osteoporosis or presenting with a clinical fracture or both, diagnostic evaluation is necessary and should include serum 25-(OH)D3, calcium, creatinine, thyroid-stimulating hormone, parathyroid hormone (PTH), testosterone (in men) and, of 24-hour urine, calcium and creatinine.[21–23] According to the clinical picture and suspicion, other serum measurements such as plasma cortisol, hemoglobin, white blood cell count, serum/urine protein electrophoresis, and selected other evaluations looking for secondary causes are indicated.

Only limited studies about the prevalence of secondary osteoporosis in daily practice have been published during the last decade. In patients referred for DXA in the clinical context of an osteoporosis clinic, contributors to secondary osteoporosis were already documented in one out of three postmenopausal women with osteoporosis.[21] In the group of otherwise presumably healthy women, previously undiagnosed contributors were found in an additional 30% of women.[21] In women and men presenting with a clinical fracture at the emergency unit and having BMD osteoporosis, 42% had contributors to secondary osteoporosis, mainly vitamin D deficiency.[22]

Vitamin D deficiency is endemic worldwide[24] but is not included in the FRAX algorithm. Vitamin D deficiency was found to be the main contributor to secondary osteoporosis in postmenopausal women with BMD osteoporosis,[21] in women and men presenting with a clinical fracture and having BMD osteoporosis,[22] and in patients presenting with a hip fracture.[25] Recent data indicate that vitamin D is an independent risk for fractures,[26] and meta-analyses indicate that correction of vitamin D deficiency results in a decreased fall and fracture risk,[27,28] but the effects depend on the dose of vitamin D and the target population.[29] Frail older people confined to institutions may sustain fewer hip fractures if given vitamin D with calcium. Vitamin D alone is unlikely to prevent fracture.[30]

It is still a matter of debate which dose of vitamin D3 (or potentially D2) supplementation is necessary/optimal, taking into account baseline vitamin D status and the desired serum levels to be achieved by supplementation.[31–33] Clearly, an intake of 400 IU/day is not sufficient.[31–34] A daily intake of 800 to 1,600 IU in healthy adults will increase serum levels above 75 nmol/L in half of the population.[33] Others suggest that 1,000 to 1,200 IU/day is necessary in addition to typical food and cutaneous inputs to achieve a target serum level of 80 nmol/L (32 ng/mL).[31]

Lifelong milk intake is not related to fracture risk,[35] but in several reviews, the necessity of addition of calcium to vitamin D for fracture prevention was stressed and a dose of 1,000 to 1,200 mg/day was advocated.[34,36] However, in studies published in 2008, supplements of 1,000 mg calcium/day in healthy postmenopausal women[37] and healthy men[38] with a mean baseline calcium intake of 800 mg/day were associated with an increased risk of vascular events, including myocardial infarction. These studies raised considerable controversy and suggested the need for further research.[39] In this context, it is reassuring that, when intake of vitamin is sufficient, the need for D3 calcium intake is considered to be lower.[32,40–42] Indeed, if dietary calcium is a threshold nutrient, as suggested by Heaney,[41] then the threshold for optimal calcium absorption may be at a lower calcium intake when vitamin D nutrition is higher. Until well-designed studies address the current uncertainties, the possible detrimental effect (for example, hypercalcemia and its complications) of higher-than-recommended calcium intake should be balanced against the likely benefits of calcium on bone, particularly in older women.[43] It should be noted that all clinical trials with drug therapy for osteoporosis (bisphosphonates and so on) have been conducted with the concomitant use of calcium and vitamin D supplementation.

It is generally considered that secondary causes of osteoporosis are more common in men than women, with the exception of hormone deficiency, which is characteristic after menopause, whereas andropause, depending on its definition, is found in only a subgroup of older men or men with osteoporosis.[44] Hypogonadism resulting from the treatment of breast and prostate cancer is recognized as an emerging clinical problem.[45] Cancer treatment-induced bone loss with adjuvant endocrine therapy with an aromatase inhibitor or androgen deprivation can be considered a risk factor for the development of osteopenia, osteoporosis, and bone fracture, which can be mitigated by appropriate bisphosphonate therapy.[45] Other, less common, risk factors for osteoporosis and fractures but commonly present in patients with low BMD or presenting with a fracture and that are not part of FRAX include the use of medications (for example, anticonvulsants, primary hyperparathyroidism, renal insufficiency, gastrectomy, Cushing syndrome, dementia, and chronic pulmonary and/or liver diseases).


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