There is no doubt about the skeletal efficacy of bone drugs as used in their registered indications: treatment of osteoporosis in males and females, Paget’s disease of bone, multiple myeloma, bone metastases, cancer-induced hypercalcaemia, prevention and treatment of glucocorticoid induced osteoporosis or bone loss after hormonal deprivation in hormone sensitive cancers as, e.g. prostate or breast. Fractures can be prevented and bone pain and progressive bone disease limited. In this manuscript, an extensive review of non-skeletal effects of these drugs is presented. These can be either beneficial or deleterious.
Beneficial non-skeletal effects are proven for vitamin D and SERMs. Fall reduction, improved muscular function and physical performance are observed for substitution with adequate doses of vitamin D (800 IU/day) in deficient populations. As the health impact of falls is broader than for fractures only, fall reduction is a separate, valuable clinical outcome. For SERMs, long-term (up to 8 years) primary chemoprevention of oestrogen receptor positive breast cancers in postmenopausal women is documented. Viewing the lower level of evidence of non-vertebral fracture reduction by SERMs compared to other anti-resorptive bone drugs, breast cancer prevention contributes to the preferred use of SERMs in a specific therapeutic niche determined by younger age, axial osteoporosis and increased breast cancer risk.
More recently, some studies illustrated a reduction in mortality (with vitamin D, SERMs, IV bisphosphonate), which was probably not related to the fracture reduction. This interesting observation requires confirmation by additional large scaled and long-term studies including specific endpoints on cardiovascular risk factors and events and cancer.
Other promising beneficial effects are described for strontium on cartilage and spinal osteoarthritis and for denosumab on the prevention of bone erosions in rheumatoid arthritis. More clinical trials are needed to validate a potential use in these therapeutic areas. Furthermore animal or observational data support some speculation on potential benefits of calcium on ischemic cardiac mortality and stroke; of vitamin D on cardiovascular outcomes, autoimmune diseases and cancer prevention and of SERMs on coronary events and of denosumab on the prevention of vascular calcification.
The most frequent non-skeletal side effects of bone drugs are the gastrointestinal intolerance of calcium supplements and oral bisphosphonates, contributing in part to the reported low adherence of these drugs, and the acute phase reactions following intravenous amino-bisphosphonates applications. More important side effects in terms of severity, but fortunately infrequent, are stroke and venous thromboembolic events for SERMs and endometrium cancer for tamoxifen. A severe cutaneous hypersensitivity reaction, described as DRESS syndrome, has been reported in extremely rare case (only 16 reported) in clinical practice with strontium ranelate, although etiologic linkage remains doubtful. Hypocalcaemia has rarely been observed in bisphosphonate and denosumab trials (including calcium and vitamin D repleted patients); moreover, it was mild, transient and asymptomatic. Some studies, but not all, report kidney stones and myocardial infarction as side effects of calcium supplements and renal toxicity for iv pamidronate and zoledronate. Speculative side effects are discussed: musculoskeletal pain, uveitis, scleritis and oesophageal cancer for oral bisphosphonates and atrial fibrillation for iv zoledronate, coronary disease for SERMs, venous thromboembolism of strontium ranelate and skin infections for denosumab.
In conclusion, some of the non-skeletal effects of bone drugs, either beneficial or deleterious, may influence treatment choices, whereas others still require more studies to reveal additional insights into remaining questions concerning the clinical management of patients with bone diseases.