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Treatment of Osteoporosis CME
Disclosures
Ego Seeman, MD, PhD
Many advances have taken place in the treatment of osteoporosis. With improvement in the quality of the design and execution of clinical trials undertaken during the past 10-15 years, inferences can be made with greater confidence regarding antifracture efficacy of more recently investigated antiresorptive drugs such as the bisphosphonates, alendronate and risedronate, and the selective estrogen receptor modulator (SERM), raloxifene. These drugs continue to be studied and some new data were presented at the 1st Joint Meeting of the International Bone and Mineral Society and the European Calcified Tissue Society. However, probably the most exciting advance that has taken place in the study of antiosteoporotic drugs concerns the accumulating evidence that the anabolic agent parathyroid hormone (PTH) and certain of its amino acid fragments can rebuild the eroded, aged skeleton. Further refinements of recently published studies as well as further evidence for its mechanism of action and its antifracture efficacy were presented at this conference.
Antiresorptive Drugs
A reduction in risk for spine fracture using alendronate, raloxifene, or risedronate is observed early in the course of treatment, within the first 12-24 months.[1-5] These drugs reduce the risk of single or multiple fractures, and they reduce the risk of symptomatic as well as morphometric (asymptomatic) spine fractures. These effects are documented in women with osteoporosis with a prevalent fracture for alendronate, raloxifene, and risedronate, but only alendronate and raloxifene have been reported to reduce the risk of spine fractures in women without a prevalent fracture. Whether the risk reduction observed with these drugs is sustained beyond 3-4 years is unclear at this time, but some evidence for a sustained effect was reported at this conference. Some evidence was also presented to suggest that risedronate reduces the risk of spine fractures in patients with osteopenia.
Nonspine fracture rates are reduced with alendronate and risedronate, but there is no evidence for this with raloxifene. The antihip fracture efficacy data are difficult to interpret, but the available evidence suggests that alendronate and risedronate are both likely to reduce the risk of hip fracture in ambulant women.[1,2,6] In the alendronate trials, hip fracture was not a primary end point, but there was consistency in the fracture risk reduction across several trials. However, event rates were low, and confidence intervals overlapped unity except in the fracture arm of the Fracture Intervention Trial (FIT) and in the subjects with osteoporosis in the nonfracture arm of FIT. In the risedronate trial, hip fractures were the primary end point, there were many events, and there was a significant reduction in fracture risk in women with osteoporosis aged 70-79 years but not in women over 80 years of age (the source of 50% of all hip fractures). Estrogen, etidronate, calcitonin, and vitamin D metabolites may prevent fracture, but, for historical and other reasons, flaws in design, execution, and analyses (small sample sizes, trial brevity, unplanned pooling of groups, subgroup analyses, selective presentation of data, dropouts, unblinding, lack of controls) make the results difficult to interpret. Several advances in the study of these agents were presented at this conference.
BisphosphonatesThe bisphosphonates are the most thoroughly investigated drugs in the field of osteoporosis. In general, the results of the trials are reported as a single figure, the risk reduction relative to controls, despite the fact that subjects range in age from 50-80 years and are treated for 3-4 years. The reduction in fracture risk is usually seen within the first 12-18 months of treatment. It is unclear whether the reduction in risk applies to all age groups and whether the risk reduction is sustained or lessens with time.
To address whether the global fracture risk reduction using alendronate was age-specific, M.C. Hochberg of the University of Maryland, Baltimore, and colleagues[7] report the relative and absolute risk reduction for the hip, spine, or forearm in 3658 women with osteoporosis from FIT. The age groups studied were: 55-65, 65-70, 70-75, and 75-85 years. The relative risk reduction for hip, spine, and forearm fractures over the trial were 53%, 45%, and 30%, respectively, and did not depend on age. The absolute risk reduction (ARR) was small in the younger age groups because of the low frequency of events and increased with advancing age. For the hip, the ARR (number per 100 patient-years) ranged from 0.13 (55- to 65-year-olds) to 0.53 (75- to 85-year-olds). The corresponding ARRs for spine fractures were 0.14 and 0.86. The number needed to treat (NNT) for 5 years for the hip fracture risk reduction was 157 for 55- to 65-year-olds and 45 for 75- to 85-year-olds. The corresponding NNTs for the spine were 140 and 23.
For a drug to be regarded as having a sustained effect, the risk reduction seen during the first 12-24 months of treatment should also be seen subsequently. Usually, results are presented as the cumulative numbers of women who fracture during 3-4 years of a study. The curves depicting the placebo and treatment diverge during the first 12-24 months, but whether they continue to do so, or become parallel, may be difficult to discern. In a 2-year extension study of the risedronate trial, D. Hosking, Nottingham City Hospital, Nottingham, England, and colleagues[8] report that treatment with risedronate for 5 years reduces fracture risk. Of the patients who completed the 3 years, 135 received risedronate 5 mg and 130 received placebo; 82% completed the study. In years 4-5, risedronate reduced the incidence of new spine fractures (risedronate, 11.1%; placebo, 22.3%; P = .011). These data are encouraging but should be interpreted cautiously, as the sample represents only a small fraction of the original sample randomized to placebo or control group.
Although anti-spine fracture efficacy of the bisphosphonates is well documented in patients with osteoporosis, the antifracture efficacy of bisphosphonates in patients with osteopenia is less clear. S.A. Quandt, Wake Forest University, Winston-Salem, North Carolina, and colleagues[9] report that alendronate reduced the risk of clinical vertebral fractures in women with osteopenia. The investigators studied 3740 women, aged 55-80 years, with bone mineral density (BMD) T-score > -2.5 at the femoral neck — 942 with an existing morphometric vertebral fracture and 2799 without; 1859 were treated with placebo and 1881 were treated with alendronate 5 mg daily for 2 years and 10 mg up to 4.5 years. Alendronate reduced the risk of clinical vertebral fractures by 60% (RR = 0.40 [0.19, 0.76]). The risk reduction was 0.34 (0.12, 0.84) in those with prevalent fractures and 0.46 (0.16, 1.17) in those without prevalent fractures. Although the point estimates do not differ much, the confidence interval for the latter overlaps unity, suggesting that alendronate may reduce fracture risk in women with osteopenia alone, but prospective studies are needed to demonstrate any benefit convincingly.
If a drug reduces the risk of fracture in patients with osteoporosis with prevalent fracture, is it reasonable to infer that the drug will be efficacious in patients without a baseline fracture? This probably cannot be inferred because fracture rates are very much higher in the former, so that the ability to demonstrate a fracture risk reduction of a drug when event rates are low requires very large sample sizes.
The studies of the anti-spine fracture efficacy of risedronate were done in patients with a prevalent fracture. To determine whether this drug reduces the risk of fracture in patients with osteoporosis without a baseline fracture, I. Fogelman, Guy's Hospital, London, England, and colleagues[10] pooled the results of the subgroups of patients with low BMD from 3 risedronate studies and the Hip Intervention Program (HIP) study. The studies ranged from 1.5-3 years in duration and included 383 patients ranging in age from 63-71 years with no prevalent vertebral fracture and a spinal BMD T score less than -2.5 SD. Risedronate reduced the risk of a first vertebral fracture by 70%. These results should be viewed with caution, as they are derived from post-hoc analyses of studies designed to examine the effect of risedronate on BMD, not fractures. Small numbers resulted in wide confidence intervals even though the point estimate for risk reduction favors the drug.
Gastrointestinal Effects of BisphosphonatesThe bisphosphonates may result in upper gastrointestinal (GI) irritation. A great deal of debate continues regarding the relative safety of alendronate and risedronate. P.D. Miller, Colorado Center for Bone Research, Lakewood, Colorado, and colleagues[11] examined the upper GI tolerability of alendronate and placebo in postmenopausal women with osteoporosis who discontinued alendronate because of an upper GI adverse experience. Subsequent rechallenge with alendronate or placebo in a double-blind, randomized, parallel-group, placebo-controlled administration of alendronate 10 mg daily or placebo daily for 8 weeks resulted in a cumulative incidence of patients who discontinued because of upper GI intolerance of 14.5% (alendronate, n = 88) and 17.3% (placebo, n = 84). The data suggest that cautious re-exposure to treatment is a reasonable approach given that tolerance to treatment was achieved in about 85% of the subjects.
In a 2-week study, A.B.R. Thomson, University of Alberta, Edmonton, Alberta, Canada, and colleagues[12] compared gastric ulcer incidence after treatment with risedronate (5 mg, n = 318) or alendronate (10 mg, n = 317) in healthy postmenopausal women stratified by Helicobacter pylori (HP) status. Subjects were randomized to risedronate (5 mg, n = 318) or alendronate (10 mg, n = 317). Evaluator-blind assessment of the esophageal, gastric, and duodenal mucosa was performed at baseline and on days 8 and 15. The overall incidence of gastric ulcers (> 3 mm) was 6.0 vs 12.1% in the risedronate vs alendronate groups, P < .05). In HP-positive subjects, gastric ulcer incidence was 3.9 vs 13.9% (P < .05). In HP-negative subjects, gastric ulcer incidence was 6.7 vs 11.5% (NS). Ulcers greater than or equal to 5 mm were noted in 3.3 vs 7.7%. Mean gastric endoscopy scores at days 8 and 15 were lower in the risedronate group (P < .001). Mean esophageal and duodenal endoscopy scores were similar in the 2 groups at days 8 and 15. Clinical upper GI adverse events occurred in more subjects receiving alendronate (8.8% vs 5.7%, n = 18). The investigators report that HP did not increase the incidence of bisphosphonate-related GI injury.
S. Adami, Clinicizzato di Valeggio, Valeggio, Italy, and colleagues[13] blindly randomized 66 postmenopausal women who discontinued alendronate 10 mg/day as a result of upper GI adverse events to risedronate (5 mg/day, n = 35) or placebo (n = 31) for 3 months. The investigators found that 16.1% of patients in the placebo group and 11.4% in the risedronate group discontinued because of upper GI adverse events. The percentage of patients reporting any upper GI adverse event was similar between the 2 groups (19.4% and 20% for placebo and risedronate, respectively). Although the authors conclude that risedronate is as well tolerated as placebo in patients who could not tolerate alendronate, the inference that this drug is better tolerated than alendronate cannot be made from this study; given that 80% of subjects with GI intolerance during alendronate therapy tolerate the medication on re-exposure, an alendronate arm should have been included as well.
Given the common occurrence of upper GI irritation in the community and the tolerance of bisphosphonates on re-exposure, the interpretation of short-term studies lacking a positive (nonsteroidal anti-inflammatory agents) or negative (placebo) control group is difficult. In a systematic review of available evidence, B. Cryer, University of Texas Southwestern, Dallas, and D. C. Bauer, University of California, San Francisco,[14] report that endoscopy trials that were appropriately blinded and of longer duration (4-10 weeks) found no difference between alendronate and risedronate or placebo, even at the higher doses used for once-weekly dosing or to treat Paget's disease. Randomized, blinded, controlled trials with clinically relevant GI end points, in which large numbers of patients participated for up to 7 years, were regarded as the highest level of evidence. The incidence of upper GI irritation complaints was about 30% in these studies and was comparable to that for placebo. Further, the incidence of worrisome upper GI irritation events was low and comparable to that seen with placebo. Two studies of patients who previously had intolerance to bisphosphonate reported that most (about 85%) were able to continue alendronate or risedronate when treatment was resumed, and the permanent discontinuation rates were no higher than with placebo. The authors infer that any increase above placebo in clinically relevant upper GI problems related to bisphosphonate use is very low.
EstrogenHormone replacement therapy (HRT) has been used for many years in the treatment of osteoporosis. However, for all of its popularity, the efficacy of HRT in preventing spine and nonspine fractures is based more on opinion than on evidence. There are only 2 prospective placebo-controlled trials examining the anti-spine fracture efficacy of estrogen.[15,16] Lufkin and colleagues[15] reported that transdermal estrogen resulted in an increase in BMD during 1 year. Eight fractures occurred in 7 of 34 women (21%) given HRT, while 20 fractures occurred in 12 of 34 women (35%) given placebo. The reduction in fracture events was significant, but the reduction in numbers of patients with fractures was not. In the study by Lindsay and colleagues,[16] vertebral deformities were less common among patients treated with the estrogen, mestranol, than among controls.[16] Among 42 placebo-treated and 58 estrogen-treated women reviewed after 6-12 years, 16 placebo-treated patients (38%) lost a mean of 0.9 cm in height, while 2 (3.4%) lost height in the HRT-treated group.
Reduction in nonvertebral fracture risk with HRT has not been assessed in a well-conducted, prospective, double-blind, randomized, controlled study. The view that HRT reduces nonvertebral fractures, including hip fractures, is based on retrospective and prospective cohort studies, or case-control studies. In all of these studies, the possibility that healthier individuals (who fall less frequently or have higher bone density) received treatment cannot be excluded.
At this conference, D. J. Torgerson and S. E. M. Bell-Syer, University of York, England,[17] examined the effects of HRT on nonvertebral fractures in a meta-analysis of 23 trials involving over 8000 patients. There was a 21% reduction in nonvertebral fractures, (RR = 0.79 [0.68-0.93]). Among women younger than 60 years, there was a significant 36% risk reduction (RR = 0.64 [0.49-0.83]), but for those older than 60 years, the risk reduction was 9% (RR = 0.91 [0.74-1.12, NS]). As most nonvertebral fractures occur in women older than 60 years, these data do not support the use of HRT in this age group.
L. Mosekilde, Aarhus University Hospital, Aarhus, Denmark, and colleagues[18] report the results of a prospective, controlled, cohort trial of 2016 women aged 45-58 years randomized to HRT (n = 502) or not (n = 504), and a nonrandomized arm on HRT (n = 221) or not (n = 789) by choice. After 5 years, 156 fractures were sustained by 140 women; 51 forearm fractures occurred in 51 women. By intention-to-treat analysis (n = 2016), the overall fracture risk reduction was 27% (RR = 0.73, [0.50-1.05, NS]), and the forearm fracture risk reduction was 55% (RR = 0.45 [0.22-0.90]). Restricting the analysis to women who had adhered to their initial allocation of HRT (n = 395) or no HRT (n = 977) showed a reduction in the overall 49% fracture risk reduction (RR = 0.61 [0.39-0.97]) and forearm fracture risk reduction of 76% (RR = 0.24 [0.09-0.69]).
Estrogens must be administered with a progestin in women with an intact uterus. The question of whether there may be beneficial effects of progestins on bone is unclear. There is little evidence for an independent effect of medroxyprogesterone on bone. J.A. Simon, George Washington University School of Medicine, Washington, DC, and colleagues[19] report that norethindrone acetate (NA) may have an independent effect on bone turnover markers. In a 1-year, double-blind, placebo-controlled, parallel-group, multicenter study, 945 subjects were randomized to placebo, 5 or 10 mcg ethinyl estradiol (EE) alone; 0.25 mg or 1 mg NA plus 5 mcg EE; 10 mcg EE plus 0.5 mg or 1 mg NA, and unmasked 0.625 conjugated equine estrogen (CEE) plus 2.5 mg medroxyprogesterone acetate. All subjects treated with EE alone or in combination with NA had significant decreases in all markers. For both doses of EE, the combination with 1 mg NA produced the largest decrease in markers. Whether the combination therapies increased BMD or reduced fracture rates more effectively than estrogen alone was not reported. Until superior antifracture efficacy is reported, there does not seem to be justification for using this progestin as a bone-sparing agent in hysterectomized women.
SERMsH. Pols, Erasmus University, Rotterdam, The Netherlands, and colleagues[20] report that raloxifene had a sustained effect, decreasing the risk of spine fractures into the fourth year of the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The cumulative RR of new vertebral fractures was 0.61 (0.51, 0.73) with the pooled doses. In the first year, raloxifene, 60 mg, decreased the incidence of new clinical spine fractures in the total sample (RR = 0.32) and in women with prevalent spine fracture (RR = 0.34). In the total MORE population, treatment with raloxifene, 60 mg, reduced the incidence of new vertebral fractures from baseline to year 3 (RR = 0.65 [0.53, 0.79]) and during the fourth year (RR = 0.61 [0.43, 0.88]). This dosage reduced the incidence of new spine fractures in women with and without prevalent spine fractures, from baseline to year 3, which was sustained in the fourth year.
P. M. Doran, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, and colleagues[21] suggest that in men the effect of raloxifene on biochemical markers of bone remodeling is determined by the circulating level of estrogen. The investigators gave raloxifene (60 mg/day) or placebo to 50 elderly men (mean age, 69 years) for 6 months. Although the mean change in urinary N-telopeptide of type I collagen (NTx) did not differ between the groups, the change in NTx correlated with serum estradiol level in the raloxifene group (r = 0.57, P = .004) but not in the control group. Men in whom NTx decreased had a lower level of estradiol at baseline than did the men in whom urinary NTx excretion did not change or increased after raloxifene — 22 +/- 2 pg/mL vs 30 +/- 3 pg/mL, respectively; 26 pg/mL defined a baseline estradiol level above which raloxifene tended to increase urine NTx excretion. Thus, the effect of raloxifene on bone resorption in elderly men may be dependent on endogenous estradiol levels.
Lasofoxifene, a new SERM, inhibits bone loss in ovariectomized (OVX) rats. R. Brommage, Wake Forest University, Winston-Salem, North Carolina, and colleagues[22] report that lasofoxifene has similar actions in adult female cynomolgus monkeys. Specifically, the investigators found that lasofoxifene inhibits the increases in bone turnover and bone loss after OVX in adult monkeys without producing uterine hypertrophy.
Vitamin DM. Billsten, Hassleholm-Kristianstad Hospital, Kristianstad, Sweden, and colleagues[23] report that administration of 3 drops of vitamin D per month reduces fracture risk in elderly women living in nursing homes. In the study, 2404 women 50 years of age and older (mean age, 85.8 years) living in 174 nursing homes were followed for 3 years; 1594 women (mean age 85.7 years) were assigned to 21,000 IU vitamin-D3 once per month. The doses were given as 3 drops of ergocalciferol (294,000 IU/mL) per month. There were 854 controls (mean age, 85.9 years). After 12, 24, and 36 months there were 120, 186, and 220 fractures, respectively. The odds ratio during the first 12, 24, and 36 months for fracture was 0.66 (0.46-0.93), 0.79 (0.59-1.6), and 0.85 (0.65-1.11).
Mechanism of Action of Antiresorptive Agents
Antiresorptive agents slow progression of bone fragility; they are unlikely to restore lost bone, architecture, or strength. BMD increases as a result of filling of the remodeling space and more complete secondary mineralization of the existing bone. There is no evidence of trabecular thickening, production of new trabeculae, or cortical thickening resulting from bone formation on the periosteal (outer) or endocortical (inner) surfaces of the cortical shell. There is some evidence that risedronate or etidronate treatment yields a less negative or a positive basic multicellular unit (BMU) balance. These agents have been reported to reduce the depth of bone resorption (perhaps by reduction in osteoclast life span) and perhaps increase bone formation (by prolongation of osteoblast life span). Whether this change at the level of the BMU will result in a positive bone balance and progressive thickening of trabeculae remains speculative.
The reversible remodeling space is the deficit in bone mass present because of the normal delay in the initiation and slower completion of bone formation that follows bone resorption. In steady state, the remodeling space deficit is "invisible" because newly excavated bone remodeling units, or BMUs, are forming and others are at various stages of being filled in. It is only when a perturbation occurs, such as commencement of treatment with an antiresorptive drug, that the balance changes between the number of sites being excavated and the number of sites being filled.
The antiresorptive drugs reduce the number of new cavities formed (activation frequency), so that the filling of the large numbers of excavated sites present before treatment is not matched by the creation of the same large numbers of remodeling units. The increase in BMD that results with treatment is a consequence of the completion of bone formation, rapid primary and slower secondary mineralization of the many remodeling units generated in the cycles before treatment was initiated.
Thus, the increase in BMD that occurs with antiresorptive therapy is probably determined by the rate of remodeling before treatment and the degree of suppression of remodeling by the therapy — the higher the baseline remodeling and the greater the suppression, the greater the rise in BMD. But this increase in BMD results from the increased mineral content of the bone present within the confines of existing periosteal and endosteal envelopes. No new bone is made. The cortices do not become thicker, the trabeculae do not increase in thickness or number. The newly laid down bone undergoes more complete secondary mineralization. In addition, regions of bone that would be remodeled instead undergo even more complete secondary mineralization, increasing the mineral content of existing bone further. This process likely explains the continued increase in BMD seen for some years during bisphosphonate therapy. Whether the early increase in mineral content accounts for the reduction in fracture rate is unknown. It is possible that protracted suppression of remodeling with more complete secondary mineralization of bone may reduce the elasticity and increase the brittleness of bone predisposing to microfractures. There is a correlation between the degree of suppression of bone remodeling (activation frequency) and the density of microcracks.[24]
When steady state is restored during 12-24 months of treatment, bone loss will occur provided that there is an imbalance between bone formation and resorption at each newly created remodeling site. However, if remodeling is very slow, this bone loss will be very slow and will remain undetectable. If secondary mineralization of existing bone continues, the negative bone balance at each BMU may be overcompensated by the continued increase in bone mineral within quiescent bone, and the net result may favor an increase in BMD. In other words, if the imbalance in the BMU is abolished, bone loss will cease, and the slower bone remodeling with more complete secondary mineralization is likely to increase BMD. Whether this modifies bone strength, however, is unknown.
If a second drug is added to treatment after steady state is achieved, then the smaller remodeling space may decrease further. For this reason, the demonstration of increased BMD with combined therapy and further suppression of bone remodeling markers cannot be interpreted as necessarily benefiting the skeleton in terms of its strength.
Even if there is a positive bone balance within each remodeling unit, it is difficult to conceive how each little deposit of bone will produce thicker trabeculae when the remodeling rate is suppressed; there will be too few remodeling sites formed to subsequently be "overfilled" to produce thicker trabeculae. In the histomorphometric studies published to date, there is no evidence of an increase in trabecular bone volume with alendronate, risedronate, estrogen, or raloxifene. All of these agents increase the mineral content of the existing mass of bone; calcium supplementation is likely to do the same.
Anabolic Therapy for Osteoporosis
The anabolic effects of PTH have been known to exist for about 70 years or more. Only in the past 5-10 years have data emerged that provide very consistent and encouraging results in animals and humans. Two important studies[25,26] have been published recently that suggest this drug will be useful in the management of osteoporosis.
In brief, Neer and colleagues[25] randomly assigned 1637 postmenopausal women with prior vertebral fractures to 20 or 40 mcg of rhPTH(1-34) or placebo administered subcutaneously daily. New vertebral fractures occurred in 14% of the placebo group and in 5% and 4% of the women in the respective treatment groups. The relative risks in the 2 treatment groups compared with placebo were 0.35 (0.22-0.55) and 0.31 (0.19- 0.50), respectively. Nonvertebral fragility fractures occurred in 6% of the placebo group and in 3% of those in each treatment group (0.47 [0.25-0.88] and 0.46 [0.25 - 0.86], respectively). The respective dosages increased BMD over placebo by 9% and 13% at the spine and by 3% and 6% at the femoral neck; the 40-mcg dose regimen decreased BMD at the radius shaft by 2% more than placebo. Both dosages increased total body bone mineral content by 2% to 4% more than placebo. The 40-mcg regimen increased BMD more than the 20-mcg regimen but had similar effects on the risk of fracture.
Cosman and colleagues[26] reported that spine fractures were reduced in 27 women given PTH(1-34) at 400 U (25 mcg) per day for 3 years and receiving HRT for at least 2 years prior, compared with 25 women receiving HRT alone. The percentage of women having spine fractures was 37.5% in the HRT group and 8.3% in the combined HRT and PTH group (15% height reduction criterion) or 25% to 0% (20% height reduction criterion) (P < .02 for both). BMD increased by 13.4% at the spine, 4.4% in the total hip, and 3.7% in the total body and remained stable 1 year after discontinuation.
At the conference, G. Goemaere, Ghent University Hospital, Ghent, Belgium, and colleagues[27] report a further analysis of the study published by Neer and coworkers. For the 55 women with 1 or more moderate or severe fractures, the risk reduction for fracture was 0.10 (0.04- 0.3) and 0.22 (0.1- 0.4) for the rhPTH( 1-34) 20-mcg and 40-mcg groups, respectively. Among patients with new vertebral fractures, reports of new or worsening back pain and changes in height were compared across treatment groups. PTH decreased the incidence and severity of vertebral fractures and the clinical sequelae of fracture. Of patients in the placebo, 20 mcg PTH, and 40 mcg PTH groups, 14%, 5%, and 4%, respectively, reported new spine fractures. Fewer patients in the treatment groups reported back pain (45% in the placebo group vs 23% and 21% in the treatment groups) and lesser mean height loss (1.1 cm vs 0.2 cm and 0.3 cm.)
In another analysis of the study by Neer and colleagues, E. F. Eriksen, Aarhus Amtssygehus, Aarhus, Denmark, and coinvestigators[28] reported that 1 or more incident (fragility and nonfragility) nonvertebral fractures occurred in 119 women (7.3%). Relative to women receiving placebo, those receiving 20 or 40 mcg rhPTH (1-34) had a reduced risk of nonvertebral fractures: 0.65 (0.43-0.98) and 0.60 (0.39-0.91), respectively. Of the patients with fractures, 58 were judged to have had fragility fractures. Compared with placebo, the relative risks for fragility fractures were 0.47 (0.25-0.88) and 0.46 (0.25-0.86), for the 20- and 40-mcg groups, respectively; 20- and 40-mcg doses reduced the risk of overall nonvertebral fractures (35% and 40%, respectively) and nonvertebral fragility fractures (53% and 54%, respectively).
C.D. Arnaud, University of California, San Francisco, and coworkers[29] reported the results of a 2-year, randomized, double-blind study comparing the effect of subcutaneous hPTH 1-34 (400 IU/day) added to CEE 0.625 mg daily; 74 were randomized to receive PTH or placebo. At 2 years, PTH and placebo injections were discontinued, the blind was broken, and participants were followed for an additional year. A total of 60 subjects (81%) completed the treatment phase, and 56 (76%) completed the observational phase. At 24 months, BMD at the spine increased by 29% and at the hip by 11%.
The structural basis of the fracture risk reduction with PTH is uncertain, but there is a great deal of evidence supporting the notion that intermittent PTH administration results in increased periosteal apposition and endosteal (endocortical, trabecular) surface apposition. L. Hyldstrup,[30] Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark, used digital x-ray radiogrammetry (DXR) to measure cortical thickness at baseline and at 1 year in 40 postmenopausal women with osteoporosis. Twelve patients received placebo and 28 received either rhPTH(1-34) 20 or 40 mcg administered subcutaneously once daily. Pooled analysis suggests that PTH increases the outer bone diameter (P = .016) and decreases the inner diameter (P = .08), compared with placebo.
Structural properties of the cortical bone of the proximal radius were assessed by peripheral quantitative computed tomography (pQCT) by J.R. Zanchetta, Instituto de Investigaciones Metabolicas and USAL University School of Medicine, Buenos Aires, Argentina, and colleagues,[31] in women randomly assigned to placebo, 20 mcg, or 40 mcg rhPTH(1-34) for up to 2 years. In the patients who received PTH treatment, greater periosteal circumference and cortical area, similar bone mineral content, and lower BMD were observed. The authors state these differences resulted in greater polar and axial moments of inertia and torsional bone strength index, which are predictive of increased strength. The greater periosteal distribution of cortical bone may contribute to the reduction in nonvertebral fractures.
R. M. Locklin, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, and colleagues[32] examined the mechanisms that may be responsible for the anabolic and catabolic effects of PTH. RANK ligand (RANKL) and osteoprotegerin (OPG) are produced by stromal-osteoblastic cells and regulate osteoclast formation (OCF). RANKL binds to its receptor RANK on osteoclast lineage cells but is inhibited when it binds to the soluble decoy receptor, OPG.
Marrow aspirates from C57 BL/6 mice were cultured for 5 days and PTH(1-34) (10 nM) was administered continuously or intermittently. OCF was nonexistent in controls; it was very low with intermittent treatment but frequent with continuous treatment. Intermittent treatment stimulated increases or trends toward increases in expression of osteoblast differentiation genes and IGF-I. Conversely, there were increases in OCF with continuous treatment that were associated with a 12-fold increase in the RANKL/OPG ratio. Thus, the investigators conclude that selective activation of IGF-I with intermittent treatment and of RANKL with continuous treatment regimens may explain the anabolic and catabolic responses to PTH.
Finally, M. Sato, Lilly Research Laboratories, Indianapolis, Indiana, and colleagues[33] compared the effects of statins and PTH in osteopenic, ovariectomized (OVX) mature rats. Whereas PTH increased whole body bone mineral content and restored bone mass, architecture, and strength at both cancellous and cortical bone sites in a dose-dependent manner to levels greater than OVX, sham-OVX, and baseline controls, there was no effect of statins on whole body bone mineral content, proximal tibial metaphysis, lumbar vertebra, or the femoral midshaft. The investigators found no evidence to suggest that cerivastatin or simvastatin stimulates new bone formation.
Comment
In summary, the antiresorptive agents increase BMD by increasing the bone mineral content of the existing bone; they do not alter the macro- and microarchitecture of bone. Anabolic agents may achieve this goal. Intermittent PTH administration has now been reported to reduce the risk of vertebral and nonvertebral fractures. In animal studies, this drug increases periosteal and endocortical apposition, cortical thickness, trabecular thickness, and perhaps trabecular numbers and connectedness. The structural changes are accompanied by increased bone strength and seem to diminish after cessation of treatment; however, coadministration or later addition of some antiresorptive agents may maintain the structural changes achieved by PTH. We have a great deal to learn, but the use of intermittent PTH, alone, or in combination with the antiresorptive agents, is an important and welcomed advance in the treatment of bone fragility.
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