by Dr Geoffrey Modest
The American College of Physicians just updated their clinical practice guideline on the treatment of low bone density/osteoporosis to prevent fractures in women and men (see doi:10.7326/M15-1361).
–bisphosphonates: high quality evidence that they reduce vertebral, nonvertebral and hip fractures in postmenopausal osteoporotic women (specifically shown with alendronate, risedronate, and zolendronic acid; ibandronate shown to reduce radiologic vertebral fractures; zoledronic acid reduces vertebral fractures in osteoporotic men). [BUT, these differences in bisphosphonates probably reflects the studies that have been done and may not indicate true differences between these meds. eg, we tend to assume that all ACE inhibitors are similar without specific studies showing true equivalence. Though it may not be true…..]. Adverse events: low-quality evidence that they can be associated with atypical subtrochanteric fractures (FDA issued warning), though very uncommon, in 1.78/100K in women taking bisphosphonates for <2 years, and up to >100/100K if >7 years (though these numbers pale in relation to fractures prevented in high risk patients). also, low quality evidence for osteronecrosis of the jaw (also rare). older concerns about atrial fibrillation were not found in newer studies. similarly with MI. but high-quality evidence of association with mild upper GI symptoms; hypocalcemia, flu-like symptoms, uveitis, and episcleritis with zoledronic acid; myalgias/joint symptoms with ibandronate and zoledronic acid. uncertain risk for cancer
–denosumab (monoclonal antibody which prevents the development of osteoclasts through RANKL inhibition): high quality evidence that it reduces radiographic vertebral, nonvertebral and hip fractures in post-menopausal women. Adverse events: high-quality evidence for mild upper GI symptoms; moderate quality evidence of increased risk of infection, (eg bacterial cellulitis, though no increase in serious infections); rash/eczema. also rate atypical femoral fracture and osteonecrosis of the jaw through 8 years of therapy
–teriparatide (hormone fragments of PTH): high quality evidence that it reduces radiographic vertebral and nonvertebral fractures in post-menopausal women. Adverse events: high-quality evidence of association with mild upper GI symptoms, headache, hypercalcemia. also renal effects, hypercalciuria.
–SERMs (selective estrogen receptor modulators): high quality evidence that raloxifene reduces vertebral fractures in osteoporotic women, but non-statistically-significant decrease in risk of nonvertebral or hip fractures. Adverse events: high-quality evidence of hot flashes, thromboembolic events (incl pulmonary embolism, cerebrovascular death)
–estrogens: moderate quality evidence that it does not reduce fractures in postmenopausal women (a change in recommendations, based on newer data on postmenopausal women with established osteoporosis). Adverse events: high-quality evidence of association with cerebrovascular and thromboembolic events; higher incidence of breast cancer
–calcium and vitamin D: moderate quality evidence that calcium or vitamin D alone has uncertain effect on fracture risk. Adverse events: probably no increase in MI with calcium (though shown in one analysis). increased risk of hypercalciuria with vitamin D
–physical activity: insufficient data to show conclusively that there is benefit for preventing fracture risk. no studies looking at comparative benefit of physical activity vs other interventions [though data show that physical activity can regulate bone maintenance and stimulate bone formation, increasing mineral content, and improving muscle strength (which protects the bone)]
–comparative benefits of above meds: insufficient head-to-head studies. and network meta-analysis to assess likely differences between meds did not find any
–offer pharmacotherapy for women with known osteoporosis with alendronate, risedronate, zoledonic acid, or denosumab, to reduce risk of hip and vertebral fractures. strong recommendation, high-quality evidence
–treat osteoporotic women with pharmacologic therapy for 5 years. weak recommendation, low-quality evidence. the studies to support this excluded patients with severe osteoporosis (total hip BMD in the beginning T-score worse than -3.5), or whose total hip BMD at 5 years was lower than their baseline. and post-hoc analysis found that those with pre-existing fractures or T <-2.5 after 5 years of therapy may benefit from continued treatment
–offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. weak recommendation, low-quality evidence
–do NOT do bone mineral density (BMD) monitoring during the 5-year drug treatment period for osteoporosis in women. weak recommendation, low-quality evidence.
–do NOT use estrogens or raloxifene in post-menopausal women in the treatment of osteoporosis. strong recommendation, moderate-quality evidence
–make decision whether to treat women >65yo with osteopenia who are at high risk for fracture based on discussion, fracture risk profile, and benefits/harms/cost of meds. weak recommendation, low-quality evidence (there are some studies on post-hoc analysis suggesting those with T scores near the osteoporosis range finding that treatment with risedronate significantly reduced the risk for fragility fractures by 73%
–osteoporosis is exceedingly common: 200 million people worldwide, and 54 million in the US have osteoporosis or low bone density (50% of Americans >50yo are at risk for osteoporotic fractures). also, huge economic impact on health care system: $25.3 billion/yr by 2025.
–risk factors (per the article): age, female sex, menopause, hypogonadism or premature ovarian failure, low body weight, history of parental hip fracture, ethinicity (white people at higher risk), prior fracture (clinical or not), prior fracture with minimal trauma (“fragility” fracture), rheumatoid arthritis, smoking, alcohol (>2 drinks/d), low BMD, vitamin D deficiency, low calcium intake, hyperkyphosis, falling, immobilization, long term use of some meds (glucocorticoids, anticoagulants, anticonvulsants, aromatase inhibitors, cancer chemotherapies, gonadotropin-releasing hormone agonists). by the way, older studies have suggested that the compilation of risk factors of body weight/BMI, smoking, alcohol, and ethnicity only account for aoubt 15% of the risk variability (ie, patients with lots of these risk factors may well have normal BMDs and vice versa)
–BMD definitions: T-score in postmenopausal women and men >50yo is 2.5 SD below the young female adult mean (reported as worse than -2.5). BUT only 1/2 of the people with osteoporotic fractures have this low a BMD (which is probably because the BMD is a quantitative assessment of the amount of calcium in a cross-section of bone and does not reflect the internal qualitative structure of the bone). And, on the other side, osteoporotic patients on bisphosphonates with no improvement in BMD still have large reductions in fractures. There is also the Z-score, which compares people to those of the patient’s age and sex, and those better than -2.0 are “within the expected range for age”. The FRAX score (see https://www.sheffield.ac.uk/FRAX/tool.jsp and has been used about 5 million times, per the website) combines clinical risk factors, which can include BMD but does not need it, though data on benefit of FRAX are lacking. the threshold to treat varies by health care system and by clinical judgment, but rough guidelines, eg from the North American Menopause Society (see osteoporosis NAMS 2010 in dropbox, or DOI: 10.1097/gme.0b013e3181cdd4a7) is at least 20% for major osteoporotic fracture or at least 3% for hip fracture.
–in terms of physical activity, there are a slew of observational studies showing benefit, reasonable mechanistic support (the more one stresses one’s bones, the stronger they are; and conversely the less stressed, as through immobilization or prolonged bed rest esp in the elderly, the weaker). But it turns out that drug companies, the major sponsors of studies these days, are less interested in this nonpharmacologic modality. and, practically, it is probably unethical to randomize people to exercise vs not and follow them for years, given the multitude of exercise benefits, physically and mentally… and there are no real comparative effectiveness trials of the different meds because, I would guess, drug companies choose the low bar of placebo control for their studies instead of comparing to another active med in order to maximize the likelihood for benefit and FDA approval.
–also, there really are limited data on treatment of men
— I would also add to the list of risk factors: HIV and some HIV meds (eg tenofovir disoproxil fumarate) and renal failure, as well as other medical conditions (hyperparathyroidism, monoclonal gammopathy and myelomas, etc)
–in terms of stopping therapy, I have been repeating the BMD after 5 years of therapy and continuing with bisphosphonates if the T-score is worse than pre-treatment or if it is more than about -2.5 to -2.7, after discussion with patients. I am concerned that some clinicians are just stopping the bisphophonates at 5 years without reassessing the patient with another BMD, based on not knowing the exclusions or posthoc analysis of the relevant studies, which may put some patients at significant risk (see blog)
so, seems to me to be pretty reasonable recommendations overall. I do have lots of women on bisphosphonates without adverse effects, including into well-advanced age. The rationale here is that the risk of falls increases with age, as does the risk of hip osteoporosis. And the benefit of bisphosphonates in terms of fracture protection is evident within 11 months, and 8 months in those >70yo (see DOI 10.1007/s40266-016-0344-7).
see prior blog for a more detailed review of the studies on stopping bisphosphonates after 5 years.