Osteoporosis in Older People: A Tale of Two Studies (and Three Treatments)

‘‘I is the age of antiresorptives, and it is the age of anabolics. It is the epoch of densitometry, and it is the epoch of bone biomarkers. It is the season of fracture prevention, and it is the season of fracture reduction. ’’ (Apologies to Charles Dickens.) So great have been the strides in the development of therapies to prevent and treat osteoporosis that it is easy to anticipate an era with significant benefits to older people in preventing the morbidity and mortality associated with osteoporotic fractures. The studies by Boonen et al. and Agrawal et al. in this issue of the Journal encourage both optimism and caution. The successful use of parathyroid hormone (PTH) to increase bone mineral density (BMD), enhance bone quality, and reduce fractures has represented a major advance in the treatment of osteoporosis. PTH had long been conceived of as a catabolic agent that contributes to bone destruction and loss of BMD. This effect is now known to result from persistent elevation of PTH. As long ago as 1980, it was reported that intermittent injection of exogenous PTH in humans stimulated significant new bone formation. Daily subcutaneous injection of PTH increases lumbar spinal and femoral BMD in postmenopausal women and in men with osteoporosis. PTH reduces vertebral and nonvertebral fractures in postmenopausal women. PTH treatment can also reverse the loss of bone in glucocorticoid-induced osteoporosis in postmenopausal women. The presently commercially available preparation of PTH (teriparatide) is a recombinant molecule consisting of the 34 N-terminal amino acids of human PTH. Unlike antiresorptive therapies such as estrogen, raloxifene, bisphosphonates, and calcitonin that inhibit bone resorption, PTH stimulates new bone formation. PTH enhances bone quality and bone strength by increasing trabecular connectivity and the cross-sectional area of the bone. Furthermore, PTH stimulates deposition of bone in appropriate locations in the skeleton, on those surfaces that are subject to mechanical forces. Therefore, new bone is formed where it is needed. Does anabolic therapy with PTH benefit older people? A subgroup analysis of the Fracture Prevention Trial was performed and indicated that teriparatide at doses of 20 and 40 mg per day induced a greater increase in vertebral BMD in women aged 65 and older than in younger women. Vertebral fracture risk reduction was similar across age groups. Boonen et al. now extend these analyses using the Fracture Prevention Trial data to compare the effects of the approved dose of teriparatide (20mg) in women aged 75 and older with those in women younger than 75. The investigators confirm that those aged 75 and older benefit from PTH treatment. In particular, they demonstrate that there are no treatment-by-age interactions with bone turnover markers, femoral neck BMD, vertebral and nonvertebral fractures, or height loss. Just as importantly, there were no significant differences in the side-effect profile between the older and younger subjects; PTH was generally well tolerated. Therefore, we can consider using PTH with increased confidence in elderly patients. However, it is important to note the limitations of their study. The subjects were required to be ambulatory and free of major comorbidities. Because mechanical loading modulates PTHstimulated gains in new bone, would similar benefits be observed in frail older people with limited mobility? In addition, the subject groups (young, old, placebo, and treatment) all had an average 25-hydoxyvitamin D (25OHD) level greater than 75 nmol/L. There is overwhelming evidence that a large number (perhaps a majority) of older people suffer from hypovitaminosis D. There is a developing consensus that vitamin D insufficiency is present when 25OHD levels are below 75 to 80 nmol/L and that frank deficiency exists below 15 to 20 ng/mL (37.5 to 50.0 nmol/L). Consequently, the subjects in this study who received PTH differed significantly from frail older people, particularly those with comorbidities, and from older patients in institutions. Will teriparatide treatment be as effective in those who are not vitamin D replete? What about those with the common combination of poor mobility and hypovitaminosis D? As with many studies of this kind, there was excellent compliance and a low dropout rate, but in outpatient practice, long-term compliance is generally poor, particularly for diseases that are ‘‘silent,’’ such as osteoporosis. Because PTH is administered daily subcutaneously, it will likely require a high level of motivation and patient–caregiver understanding. In addition, the study does not directly address critical questions such as when PTH should be considered as a primary therapy for osteoporosis in older people or as an adjunctive therapy for those who have already received antiresorptives. While awaiting future studies, PTH therapy should be reserved for those with severe loss of BMD (T score 3.5), those with prevalent fractures and a T score of 2.5 and below, and those who continue to fracture or lose BMD after 2 years of bisphosphonate treatment. DOI: 10.1111/j.1532-5415.2006. 00699.x