Human parathyroid hormone (1-34) compared to alendronate
Forteo has recently been approved by the FDA to treat osteoporosis. This injectable fragment of human parathyroid (also called teriparatide) has been shown to stimulate bone formation when given in once-daily injections of either 20 or 40 micrograms. Alendronate (Fosamax) has also been shown to increase bone density by reducing the number and activity of osteoclasts, thus reducing bone resorption, thereby allowing a net increase in bone formation to occur. An interesting study was done prior to Forteo receiving FDA approval to compare the effects of teraparatide and alendronate in postmenopausal women with osteoporosis. See J Clinc Endocrinol Metab 2002 Oct;87(10):4528-35, A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. Body JJ and others, PMID: 12364430. Women in the study were randomized to get either once daily 40 microgram injections of teriparatide plus oral placebo, or 10 mg oral alendronate plus placebo injections for a median duration of treatment of 14 months. Increases in BMD were measured by dual-energy X-ray absorptiometry (DXA) at various intervals. Additionally, investigators studied the incidence of nonvertebral fractures along with biochemical markers of bone formation and resorption. Note: Subsequent studies have indicated that 20 microgram injections of teriparatide give the proper dose in terms of minimizing side effects while adequately increasing BMD. Thus, the results of this study will be magnified compared to what someone should expect to get with Forteo, the 20 microgram dosage. The authors concluded: "Teriparatide increased femoral neck BMD and total body bone mineral significantly more than did alendronate, but BMD at the one third distal radius decreased compared with alendronate (P<or=0.05). Nonvertebral fracture incidence was significantly lower in the teriparatide group than in the alendronate group (P<0.05). Both treatments were well tolerated despite transient mild asymptomatic hypercalcemia with teriparatide treatment. In conclusion, teriparatide, a bone formation agent, increased BMD at most sites and decreased nonvertebral fractures more than alendronate." Here are some of the interesting details of the study results:
Difference in BMD increase in the spine. At the earliest measurement of BMD, the percentage increase in lateral spine BMD (LS-BMD) for the teriparatide group was 2.7% greater than that in the alendronate group (P<0.001). At six months, the difference increased to 5.4%, and 8.3% at 12 months (P<0.001). The authors note, "At 3 months, teriparatide treatment had increased LS-BMD by 5.2%, an amount nearly equal to the 5.9% increase observed after treatment with 12 months of alendronate." Alendronate increased spinal bone area by 0.49 cm2 (P=0.018), while teriparatide increased spinal bone area by 1.29 cm2 (P<0.001, compared with baseline and P=0.002, compared with alendronate).
BMD changes in other regions. At 12 months, femoral neck and total hip BMD were increased more by teriparatide than alendronate. At the study's end, both alendronate and teriparatide treatments significantly increased BMD from baseline at the spine and hip, as well as increasing total body BMD. At each site the increase was greater for teriparatide than for alendronate, except at the trochanter, where results were similar. The alendronate group had no change in BMD at the ultradistal or the one third distal regions of the radius. The teriparatide group, however, showed no change in ultradistal BMD, but that of the one third distal radius decreased significantly ((P<0.001), compared with baseline and the alendronate group.
Nonvertebral fractures. Nonvertebral fractures were significantly lower in the teriparatide-treated group (4.1%) than in the alendronate group (13%, P=0.042). Five fractures occurred in the alendronate group before six months of treatment, and five occurred in the last six months or more of treatment. There were 73 women in each group, and only three women had fractures in the teriparatide group, while there were ten women who had them in the alendronate group. Note that six of these fractures occurred in the ankle, foot, and toes, areas not often associated with osteoporotic fractures. No mention is made of the severity of the trauma that caused the fractures.
Markers of bone turnover. Alendronate reduced NTX, a biochemical marker of bone resorption, and bone ALP, a marker of bone formation, by about 50%. NTX was significantly reduced at 1 month and bone ALP at 3 months, and they remained depressed throughout the study. (Note, these time periods could be important if you and your physician are monitoring your success after starting alendronate or other bisphosphonate therapy. They should give a rough guide to evaluate expected changes in your markers of bone turnover). In contrast, teriparatide significantly increased bone ALP and NTX at one month. Maximum increase (100%) occurred in bone ALP at six months, while the maximum (160% ) increase in NTX was seen at 12 months.
Adverse events. There was no difference in the proportion of women reporting adverse events between the groups. Significantly fewer patients reported new or worsened back pain in the teriparatide group (5.5%) than in the alendronate group (19.2%, P=0.012). Leg cramps were noted by six patients using teriparatide and by no one in the alendronate group (P=0.012).
Interesting outliers. The authors note, "Five patients had a decrease in LS-BMD at 12 months: two patients in the teriparatide group (-13% and -5.5%) and three patients in the alendronate group (-3.9%, -3.1%, and -2.0%)." (Editor's comment: I have received an occasional email over the years from someone taking alendronate who simply isn't gaining BMD, or is losing it. This study verifies that those people do exist, and it shows that very significant losses can occur in a small number of people taking teriparatide. Sadly, the authors didn't document if these people's biochemical markers of bone turnover would have given an early indication that the medication wasn't working as expected, or that the patient wasn't complying, or whatever else was the cause of the negative results. One would think that the biochemical markers would be suggestive that the desired increase in BMD was not occurring. This should be a heads up for anyone on approved therapy for osteoporosis that they can't just blindly assume they are building BMD).
Clinical laboratory findings. There was a transient increase in serum calcium within 4-6 hours after teriparatide injection. The median post-dose serum calcium in this group reached its maximum of 10.0 mg/dl at six months. This was significantly higher than the median post-dose serum calcium of 9.2 mg/dl in the alendronate group (P<0.001). The serum calcium elevations were asymptomatic, and weren't associated with any adverse outcomes.
Interesting points from the authors' discussion of the article. From animal studies it had been expected that teriparatide would have a positive effect on bone size as well as the well-documented positive effect on BMD. This may indicate a direct effect on cortical bone as well as an effect of bone architecture. They note that the decrease in BMD at the distal radius may be due to increased haversian remodeling which transiently increases cortical porosity but not biomechanical strength. There were no distal radius fractures in this study to help back up that statement. The method of action of teriparatide is by increasing osteoblast birth rate in the bone marrow and/or through preexisitng bone-lining cells, and by inhibiting osteoblast apoptosis (cell death). This combination results in a rapid increase in bone formation activity and bone turnover. Thus, the teriparatide increases trabecular bone volume, cortical thickness, and restores trabecular connectivity, whereas the majority of BMD increase seen in bisphosphonate therapy is due to increased mineralization of the existing bone matrix.
Editor's comments. As usual, this study was done entirely on postmenopausal women, but the results can be expected to be similar in men with osteoporosis. The apparent bottom line is that if human parathyroid hormone (1-34) is given by daily subcutaneous injection in a 40 microgram dose, BMD can be expected to increase at approximately four times the rate seen with 10 mg/day oral alendronate (Fosamax). Note, however, that Forteo is only available in a 20 microgram dose, so results shouldn't be expected to be quite so spectacular. For a report on Forteo by Eli Lilly and Company, see http://newsroom.lilly.com/news/story.cfm?ID=1143.