Human parathyroid hormone (1-34) use in men
The update for January 14, 2003 discussed the comparison of effects on bone mineral density (BMD) and other factors between teriparatide and alendronate in postmenopausal women with osteoporosis. A recent study has also looked at the effect of teriparatide when used on men with osteoporosis. See J Bone Miner Res 2003 Jan;18(1):9-17, The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. Orwoll ES and others, PMID: 8610640. This study involved 437 men with spine or hip BMD more than 2 SD below the young adult male. Men were randomized to three groups, all of which received 1000 mg calcium and 400-1200 IU of vitamin D daily. The groups at baseline included: Placebo, 147, teriparatide 20 microgram, 151, and teriparatide 40 microgram, 139. The study was stopped after a mean duration of 11 months when osteosarcomas were found in rats having routine toxicology study with life-time daily doses of teriparatide. Results showed that, "Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 microgram) and 9.0% (40 microgram) above baseline (P<0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased by 1.5% (20 microgram; p=.021) and 2.9% (40 microgram; p=0.005) above baseline in the teriparatide subjects." The authors also note, "Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake." Adverse events were similar in the placebo and 20 microgram groups, but more common in the 40-microgram group. The authors conclude: "This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men." Some of the details of the findings follow.
BMD increases. Lumbar spine BMD increased more than placebo for both teriparatide groups starting at three months and continued that way throughout the study. Approximately 40% of the placebo group lost BMD by study end, compared to 7.1% of the 20-microgram group and 6.2% of the 40-microgram group. Unfortunately, the study doesn't indicate how much BMD was lost in any of these men, but it once again points out that not everyone gains BMD when being treated with osteoporosis medications--even when the mean gain in BMD is quite high. They did, however, mention that lumbar spine BMD increased by 5% or more in 55% of those in the 20-microgram group and in 71% of those in the 40-microgram group.
Biochemical markers of bone remodeling. In the teriparatide groups markers of osteoblastic activity increased after one month of therapy (P<0.001), while those same markers were stable or declined in the placebo group. Those same markers stabilized at there maximum level after 6-12 months of therapy in the teriparatide groups. Bone alkaline phosphatase reached maximum levels of 29% and 59% above baseline in the 20- and 40-microgram groups, respectively. Bone resorption markers were stable in the placebo group and decreased in the treatment groups. Note: The rapid increase in markers of bone remodeling appears to be a tool that should be used to help find those nonresponders early in treatment and try to figure out why they aren't responding or to try other therapies.
Mineral Metabolism. As in the study covered in the January 14, 2002 update, the mean serum calcium concentrations measured at 4-6 hours after injection of teriparatide were higher compared to placebo (P<0.001). Once again, this didn't appear to be a major problem. It did require adjusting the calcium supplement dose mostly during the first 28 weeks of the trial for 4 of the 20-microgram group and 12 patients in the 40-microgram group. No reductions in teriparatide dosages were needed.
Adverse events. There were no cases of osteosarcoma, but three other types of cancer occurred in the 20-microgram group. Thirty-nine people withdrew because of adverse events: 7 in the placebo group, 14 in the 20-microgram group and 18 in the 40-microgram group. Nausea was reported by 26 patients in the 40-microgram group, but only 3.6% of the group's patients withdrew for that reason. Additionally, 15 members of the 40-microgram group reported having headaches.
Comparison to alendronate. Orwoll and others did a similar study on men recently using Alendronate. See N Engl J Med 2000, 343;604-610, Alendronate for the treatment of osteoporosis in men. Orwoll E and others, PMID 10979796. They found over the twelve-month study that men had a mean 7.1% increase in lumbar spine BMD and 2.5% mean increase in BMD at the femoral neck when taking 10 mg/day alendronate. Although the 40-microgram group of teriparatide users had greater mean spinal BMD increase of 9.0%, the 20-microgram group had 5.9% mean increase in BMD, less improvement than the men taking alendronate. But, remember the teriparatide study only went for 11 months. It does appear that the really phenomenal increases in BMD have occurred at the higher teriparatide dosage, which won't be used because of the increased adverse events.
Editor's comments. It would appear that teriparatide, which is now Forteo, might work along with a bisphosphonate and the two might be synergistic since they have different methods of action. I've not heard of any clinical trials involving this combination, but it would be interesting to see what results occur if one is done. There is precedence for trying this combination in the study by Cosman F and others, J Bone Miner Res 2001 May;16(5):925-31, Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. PMID: 11341338. This study combined HRT and teriparatide for a three-year period and compared those women to ones using only HRT. The authors found a 13.4% mean spinal BMD increase in the teriparatide group (taking 25 micrograms daily) compared to no change in the women on HRT. There was no group of women in this study taking only teriparatide, so we don't know if there was an additive effect from the HRT. Careful monitoring of biochemical markers of bone remodeling might give an indication of an added benefit of the two medications, especially if someone is already on bisphosphonates when starting Forteo. Within a month or so a big increase in markers of bone formation should occur.
Summary. This clinical trial on men with osteoporosis shows that teriparatide significantly increases hip and spinal BMD without serious side effects at the 20- microgram dose. Although fracture risk was not assessed in this study, the effects on BMD and biochemical markers of bone turnover are similar to those found postmenopausal women in a clinical trial of teriparatide. Those women had dramatic reductions in the risk of vertebral and nonvertebral fractures. See N Engl J Med 2001 May 10;344(19):1434-41, Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. Neer RM and others. PMID: 11346808.