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We examined paired iliac crest bone biopsy specimens from patients with osteoporosis before and after treatment with daily injections of 400 U of recombinant, human parathyroid hormone 1-34 [PTH(1-34)]. Two groups of patients were studied. The first group was comprised of 8 men with an average age 49 years. They were treated with PTH for 18 months. The second group was comprised of 8 postmenopausal women with an average age 54 years. They were treated with PTH for 36 months. The women had been and were maintained on hormone replacement therapy for the duration of PTH treatment. Patients were supplemented to obtain an average daily intake of 1500 mg of elemental calcium and 100 IU of vitamin D. The biopsy specimens were subjected to routine histomorphometric analysis and microcomputed tomography (CT). Cancellous bone area was maintained in both groups. Cortical width was maintained in men and significantly increased in women. There was no increase in cortical porosity. There was a significant increase in the width of bone packets on the inner aspect of the cortex in both men and women. This was accompanied by a significant decrease in eroded perimeter on this surface in both groups. Micro-CT confirmed the foregoing changes and, in addition, revealed an increase in connectivity density, a three dimensional (3D) measure of trabecular connectivity in the majority of patients. These findings indicate that daily PTH treatment exerts anabolic action on cortical bone in patients with osteoporosis and also can improve cancellous bone microarchitecture. The results provide a structural basis for the recent demonstration that PTH treatment reduces the incidence of osteoporosis-related fractures.

In rodent osteoporosis models, anabolic activity of parathyroid hormone (PTH) is preserved in the presence of antiresorptive agents. Anabolic activity is also preserved when PTH is administered to estrogenized postmenopausal women. In contrast, in the ewe treated with tiludronate, PTH-induced stimulation of bone turnover did not occur. To determine whether PTH in combination with alendronate could be a viable treatment for osteoporosis, we performed a short-term study of postmenopausal women with osteoporosis (n = 10) already on alendronate 10 mg/day to determine whether PTH could increase bone formation assessed biochemically. Patients continued alendronate alone (n = 5) or continued alendronate with 400 IU/day subcutaneous human PTH (1-34) added for 6 weeks. Subjects receiving PTH had serum and urine sampling weekly during PTH treatment and for 5 weeks thereafter. Sampling was performed approximately biweekly for subjects who had been on alendronate alone for 11 weeks. Samples were analyzed for osteocalcin (OC), propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BSAP), cross-linked urinary N-telopeptide (NTX), and free urinary pyridinoline (PYD). Markers of bone formation increased within 3 weeks in the PTH plus alendronate group, with mean peak levels at 5-7 weeks: OC 49%, p < 0.01; PICP 61%, p < 0.01; and BSAP 24%, p = 0.12. Levels returned to baseline after discontinuing PTH, with PICP declining the most rapidly. There were no significant changes at any time in the alendronate alone group. There were no increments in either urinary NTX or PYD in either treatment group throughout the observation period. The bone turnover marker changes seen with PTH plus alendronate were similar to those seen with PTH plus hormone replacement. These data suggest that: PTH can stimulate bone formation, evidenced by elevations of bone formation markers, even in the presence of a potent bisphosphonate; in the presence of alendronate, PTH-stimulated bone formation precedes stimulation of bone resorption, suggesting that PTH stimulates bone formation de novo; and the combination of PTH and alendronate may be a viable treatment option for postmenopausal women with osteoporosis.

Endocrine systems may be affected permanently by administration of supraphysiologic doses of hormone. This is a well known complication of glucocorticoid treatment where the pituitary/adrenal axis may never fully recover, especially when large doses of steroids are needed during significant physical stress. The goal of this investigation was to determine whether responsivity of the parathyroid gland was normal after use of (1-34)PTH daily as an investigational therapy for osteoporosis. Patients were all postmenopausal osteoporotic women treated with estrogen and enrolled in a 3-yr trial of (1-34)PTH by daily subcutaneous injection (400 IU/day) in addition to their estrogen therapy. A volunteer subgroup (n = 10) of this population was recruited for this investigation. All patients had an EDTA-provoked hypocalcemic challenge before beginning PTH treatment. The same patients had repeat EDTA-challenge tests at various times during the 3-yr PTH treatment trial. Three patients had 2 infusions while on PTH treatment (interim and at the end of 3 yr). Ionized calcium declined identically before and during PTH treatment in response to the EDTA stimulus. PTH(1-84) responses were identical before and during PTH therapy. Furthermore, there were no differences in 1,25(OH)2D elevation or in phosphorus reduction over the course of the EDTA infusion during daily PTH treatment. Osteocalcin levels were higher during PTH treatment, as expected, but responsivity to acute endogenous PTH elevations was the same after PTH treatment. We conclude that 1-34PTH therapy, at 400 IU/day for up to 3 yr, does not suppress parathyroid responsivity and should therefore (at least within this period of treatment) have no permanent adverse effect on the ability of the body to maintain calcium homeostasis. Additionally, there is no difference in target organ responsivity to acute endogenous elevations of PTH after exogenous PTH therapy.

Background: Small increases in bone mass are commonly seen with existing treatments for osteoporosis, which reduce bone remodelling and primarily prevent bone loss. Since these drugs reduce but do not eliminate risk of fractures, an anabolic agent that would increase bone mass and potentially cure the underlying skeletal problem is needed., Methods: We did a 3-year randomised controlled trial to find out the effects of 1-34 human parathyroid hormone (hPTH [1-34], 400 U/25 micrograms daily subcutaneously) in postmenopausal women with osteoporosis taking hormone-replacement therapy (n = 17). The controls were women taking hormone-replacement therapy only (n = 17). The primary outcome was bone-mineral density of the lumbar vertebrae, with bone-mineral density at other sites and vertebral fractures as secondary endpoints., Findings: Patients taking hormone-replacement therapy and PTH (1-34) had continuous increase in vertebral bone-mineral density during the 3 years, whereas there was no significant change in the control group. The total increase in vertebral bone-mineral density was 13.0% (p < 0.001); 2.7% at the hip (p = 0.05); and 8.0% in total-body bone mineral (p = 0.002). No loss of bone mass was found at any skeletal site. Increased bone mass was associated with a reduction in the rate of vertebral fractures, which was significant when fractures were taken as a 15% reduction in vertebral height (p = 0.04). During the first 6 months of treatment, serum osteocalcin concentration, which reflects bone formation, increased by more than 55%, whereas excretion of crosslinked n-telopeptide, which reflects bone resorption, increased by only 20%, which suggests some uncoupling of bone formation and resorption. By 6 months, there were similar increases in both markers, which gradually returned towards baseline as the study progressed. Vertebral bone-mineral density increased most during the first year of PTH treatment., Interpretation: We found that PTH has a pronouned anabolic effect on the central skeleton in patients on hormone-replacement therapy. PTH also increases total-body bone mineral, with no detrimental effects at any skeletal site. The increased vertebral mass was associated with a reduced rate of vertebral fracture, despite increased bone turnover. Bone-mass changes may be consistent with a reduction in all osteoporotic fractures. If confirmed in larger studies, these data have important implications for the treatment of postmenopausal osteoporosis.