The pharmacotherapies currently approved by the Food and Drug Administration for the treatment of osteoporosis -- estrogen, raloxifene, alendronate, and calcitonin -- are "antiresorptive" agents
that work by slowing the rate of bone remodeling. Thereby, they slow or retard bone loss.
None of these agents is capable of rebuilding bone. The small but variable increases in bone mineral density (BMD) in patients treated
with "antiresorptive" agents are not due to bone rebuilding. Instead, they are the result of contraction of the remodeling space and more
complete secondary mineralization.

The optimal goal for the treatment of osteoporosis, especially for patients who already have advanced bone loss, is to increase bone mass and bone strength to levels seen in average young women and men so as to prevent all osteoporotic fractures. Indeed, with the rapid aging of the population, there is an urgent need for a cure, not merely the
management of osteoporosis. This goal is not attainable with present pharmacotherapies.

More than 4,000 researchers gathered in St. Louis, Mo, from September 30 - October 4, 1999 for the 21st Annual Meeting of the American Society of Bone and Mineral Research (ASBMR). A number of exciting studies presented during this meeting significantly advanced our knowledge of
the pathogenetic mechanisms, genetics, epidemiology, and the diagnosis and treatment of osteoporosis and other metabolic bone diseases.

This report details some of the clinical and preclinical studies presented on the treatment of osteoporosis, and in particular highlights
exciting new advances toward the development of therapies that increase bone mass.

Low and Intermittent Doses of Parathyroid Hormone Promote Bone Formation

Daily injections of low doses of parathyroid hormone (PTH) -- an agent better known for its role in calcium homeostasis -- increase bone mass
in animals and humans. Similar increases in bone mass are promoted by the administration of PTH-related protein (PTHrP), the only other known ligand of the PTH receptor. Indeed, although constant, high levels of PTH cause increased bone resorption and osteitis fibrosa cystica, low and intermittent doses of PTH that are too small to affect serum calcium concentrations promote bone formation and increase bone mineral density at the lumbar spine and hip.

Apoptosis (cell death) is the most common (40%-60%) fate of osteoblasts (bone-forming cells) and increased apoptosis of osteoblasts and
osteocytes is a key pathogenetic mechanism mediating the adverse effects of glucocorticoid excess on bone. Conversely, prevention of apoptosis by intermittent PTH administration is a critical mechanism for the anabolic effects of this regimen. In other words, the anabolic effect of PTH can now be explained by evidence that PTH increases the life span of osteoblasts by reducing the prevalence of their apoptosis, not by affecting the generation of new osteoblasts, and perhaps by increasing the density of osteocytes.

Moreover, prevention of apoptosis by antiresorptive agents (bisphosphonates, calcitonin) provides a potential explanation for their
disproportionate effects on BMD and antifracture efficacy. The recent elucidation of the importance of osteoblast and osteocyte apoptosis in
the mechanism of glucocorticoid-induced osteoporosis and the elucidation of the mechanism of the anabolic effects of PTH on bone readily explain how PTH can be such an effective therapy in this condition.  Hence, for the first time, PTH and PTH-mimetic agents represent a pathophysiology-based approach that is rational as opposed to empirical, to developing pharmacotherapies for osteopenias -- in particular, for those in which osteoblast progenitor formation is suppressed.


Combination of Estrogen and Parathyroid Hormone Injections Produce Dramatic Increases in Bone Density in Postmenopausal Osteoporosis

Roe and coworkers from the University of California at San Francisco determined the bone-building efficacy of daily, self-administered,
subcutaneous injections of human PTH (hPTH) 1-34 (400 IU/day) plus oral Premarin® (0.625 mg/day) with or without medroxyprogesterone. All
subjects also received 800 IU of vitamin D and calcium supplements to ensure a daily calcium intake of 1500 mg. Of the 74 women randomized to receive either hPTH or placebo, 26 and 32, respectively, completed the study. Subjects were followed by monitoring lumbar spine, hip, and
forearm BMD by dual energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) in the spine and hip.

Strikingly, lumbar spine BMD measured by DXA increased more than 2 population standard deviations, and trabecular bone density measured by QCT increased in the PTH group by a median of 74% from baseline to 24 months, while it decreased 2.1% in the placebo group.[1]

These very exciting findings indicate that hPTH 1-34 and estrogen combination therapy can produce large increases in bone density at the
spine and femoral neck that are above the osteopenic range in postmenopausal women.


A PTH-Related Peptide (1-34) Analog Causes Sustained Increases in Spine and Hip BMD in Postmenopausal Osteoporotic Women in Two Separate Randomized, Placebo-Controlled Trials

Gallagher and colleagues, from Creighton University Medical Center, Omaha, Neb, and several other collaborating institutions, reported the results of two randomized placebo-controlled trials of semparatide, an analog of the PTH-related peptide (PTHrP 1-34).

Subjects were healthy postmenopausal osteoporotic women (with 64 and 63 participants, respectively). Participants received daily subcutaneous
injections of either vehicle or 12.5, 25, 50, or 100 mcg semparatide along with 1000 mg of calcium for 6 months. In either study, the subjects were followed for an additional 6 months after the termination of semparatide treatment. In the first trial, during the 6-month washout period, subjects received oral calcium alone. In the second trial,
subjects received calcium plus alendronate 10 mg/day during the 6-month washout period.

Both the 50- and 100-mcg dose of semparatide produced significant increases in lumbar spine BMD. At the highest dose of semparatide, a 5%
increase in lumbar spine BMD was detected after 3 months and a 10% increase was evident after 6 months of treatment. Total hip BMD
increased to a lesser extent, by +1.2% and +3.2%, with the 50-mcg and 100-mcg dose, respectively.

Gains in BMD were largely maintained 6 months after discontinuation of semparatide treatment, as subjects in the 100-mcg dose group of the
first trial experienced only a slight decline from 10% to 9% in lumbar spine BMD. Moreover, the gains in BMD were enhanced in the second trial by subsequent alendronate therapy. Nonetheless, one fifth of the subjects experienced asymptomatic hypercalcemia.[2]

These findings demonstrate that daily administration of semparatide acetate to postmenopausal women with osteoporosis results in rapid and significant increases in spine and hip BMD that are maintained for at least 6 months after discontinuation of semparatide and are enhanced by subsequent alendronate treatment.


Genomic and Nongenomic Actions of Estrogen Regulate Bone Remodeling

The increased rate of remodeling that follows loss of estrogen can be accounted for by increased osteoclastogenesis (formation of bone-resorbing cells) and osteoblastogenesis (formation of bone-forming cells). Increased remodeling alone can account for much of the rapid early decrease in BMD due to expansion of the remodeling space and less complete secondary mineralization.

However, it cannot explain the striking imbalance between formation and resorption that leads to the progressive loss of bone that continues
throughout life. It has been well documented that estrogen deficiency prolongs the lifespan of osteoclasts. Preclinical studies conducted by
my group and presented during the meeting show that estrogen and androgen deficiency increase osteoblast and osteocyte apoptosis in mice,
and these changes can be reversed by hormone replacement. In full agreement with these in vivo observations, we reported that 17beta-estradiol inhibits osteoblast and osteocyte apoptosis in vitro.

The antiapoptotic effect of 17beta-estradiol on osteoblasts and osteocytes requires the presence of the estrogen receptor (ER) alpha or beta.[3] Nonetheless, unlike the classical mechanism of
estrogen-receptor action that involves direct or indirect interaction with the transcriptional apparatus, the estrogen receptor-dependent
antiapoptotic effect of 17beta-estradiol is due to rapid (within 5 minutes) phosphorylation of extracellular signal-regulated kinases
(ERKs).[4]

Moreover, the antiapoptotic effect of 17beta-estradiol can be reproduced
by a membrane impermeable conjugate of 17beta-estradiol with bovine serum albumin (17beta E2-BSA). In addition, we demonstrated that the antiapoptotic effect of estrogen is mechanistically dissociable from its
transcriptional effects.[5]

These findings strongly support the contention that in states of  estrogen deficiency, loss of the transcriptional actions of the ERs is
responsible for the increased rate of bone remodeling. On the other hand, loss of their "nongenomic" antiapoptotic effects on osteoblasts,
in combination with an opposite effect on the lifespan of mature osteoclasts, is, at least in part, responsible for the imbalance between
formation and resorption and the progressive bone loss.


Activators of Non-Genomic Estrogen-Like Signalling (ANGELS): A Novel Class of Small Molecules With Bone Anabolic Properties

Based on the evidence that estrogen controls osteoblast and osteocyte apoptosis in vivo and in vitro by a nongenomic mechanism of action, we
tested the hypothesis that small molecules that mimic the nongenomic effects of estrogen may have anabolic properties on bone. For these
experiments, we chose a prototypic compound, estratriene-3-ol, a synthetic phenolic compound that differs from estradiol in that it lacks
the hydroxy group in the 17 carbon position, but binds to ERalpha with similar affinity as estradiol.

We reported that in spite of the significantly decreased transcriptional activity, this compound has similar antiapoptotic potency and mechanism
of action as estradiol on osteoblasts and osteocytes in vitro and in vivo. Like estradiol, estratriene-3-ol caused a rapid phosphorylation of ERKs (within 5 minutes) and its action required the ER, as its
antiapoptotic effect could be blocked by ICI 182,780 and could only be seen in stably transfected HeLa cells that express ERalpha or the
ERbeta, but not in the parental ER-negative HeLa cells.

The effects of this agent on bone were assessed in vivo by subcutaneously administering estratriene-3-ol every other day for 4
weeks to 4-to 5-month-old intact or estrogen-deficient ovariectomized
(OVX) female mice (n = 7-8).

Determination of BMD was performed by DXA at day 0 and at the termination of the experiment. Compression strength was determined in
lumbar vertebrae. Estratriene-3-ol administration to either estrogen-replete or estrogen-deficient mice for a month led to substantial increases in BMD
in the appendicular (12% gain in estrogen-replete and 19% in estrogen-deficient, compared with vehicle control) and axial skeleton
(10% and 9%, respectively). The magnitude of the gain was similar to that seen with intermittent PTH.

More important, the increase in spine BMD corresponded to a 30% and 70% gain in mechanical strength as determined by examining the force required to crush the fifth lumbar vertebra. In other words, the relative increase in vertebral compression strength was three and seven
times higher in estrogen-replete and estrogen-deficient mice, respectively, than the relative increase in BMD.

Estratriene-3-ol did not affect the growth of the hindlimbs, as determined by measurements of length, nor did it increase the width of
the cortices, but it almost doubled trabecular width at the metaphyses. Finally, administration of estratriene-3-ol prevented the ovariectomy-induced increase in the prevalence of apoptotic osteoblasts
and osteocytes in the murine vertebrae, as did the administration of estradiol.[6]

These studies provide proof of the principle that mechanism-specific ligands of ERs, in distinction to tissue-specific ligands (SERMs) or classical estrogen, may be an advantageous class of pharmacotherapeutic agents (truly anabolic as opposed to antiresorptive) for the management
of osteopenic states.


Therapeutic Goal for Osteoporosis: Increase Bone Mass and Strength