An Overview of Male Osteoporosis

Melissa A. Burmeister, PhD; Timothy K. Fincher, PhD, RPh; Anthony M. Todd, PharmD; Kristopher G. Virga, PhD; Mary M. Maddox, PharmD Candidate 2022

Disclosures

US Pharmacist. 2021;46(6):18-24. 

In This Article

Management

Pharmacotherapy for male osteoporosis includes oral or IV bisphosphonates and other antiresorptive agents, PTH analogues, anabolic agents, testosterone replacement, vitamin D supplementation, and other investigational therapies, such as selective estrogen receptor modulators (SERMs).[22,24] One key counseling point for pharmacists regarding risk reduction and management of osteoporosis in men is to explain the effectiveness of lifestyle modifications for preventing bone loss.

Bisphosphonates

The American College of Physicians recommends bisphosphonates as first-line treatment for reducing the risk of vertebral fracture in men with clinically recognized osteoporosis.[36] In male patients, the number needed to treat with bisphosphonates to prevent one vertebral fracture is 16 over a 2-year period.[37] Oral agents in this class include alendronate, ibandronate, and risedronate. These antiresorptive drugs slow bone breakdown by inhibiting proliferation of osteoclasts, decreasing their activity, and reducing their life span.[38] The drug is preferentially incorporated into sites of active bone remodeling, where it inhibits breakdown of hydroxyapatite, a major mineral component of bone.[38]

In dysregulated bone metabolism, increased activity of extracellular adenosine triphosphate (ATP), activation of the mevalonate pathway, and pyrophosphate-induced impairments of mineralization all favor bone resorption over bone formation.[38] Bisphosphonates are structural mimics of pyrophosphate wherein the P-O-P oxygen is replaced by carbon. This modification creates a nonhydrolyzable backbone and a much more stable molecule. The carbon also serves as a point of substitution, allowing for much variability in bisphosphonate agents. Like pyrophosphate, bisphosphonates bind to hydroxyapatite with high affinity. Whereas non–nitrogen-containing first-generation agents displace the terminal pyrophosphate of ATP within osteoclasts, nitrogen-containing second- and third-generation agents disrupt the mevalonate pathway.[38]

Bisphosphonates can cause adverse gastrointestinal (GI) effects, including esophagitis, dysphagia, abdominal pain, diarrhea, upset stomach, and heartburn. The dose should be taken immediately upon waking and at least 30 to 60 minutes before food or drink (except plain water), and the patient must remain upright for at least 30 to 60 minutes and until after the first food of the day is consumed in order to reduce the risk of esophageal irritation. One member of this class, zoledronic acid, is administered IV in patients who cannot take oral bisphosphonates because of GI issues or in whom adherence is a concern. Individual agents' package inserts provide more detailed information on dosing and monitoring parameters.[39–42]

PTH Analogues

Although two members of this class are available for use in the U.S., only one—teriparatide—is FDA approved for use in males. Teriparatide, an anabolic drug that helps build bone, may be used for primary or hypogonadal osteoporosis or as an alternative agent for glucocorticoid-induced osteoporosis.[36] Human PTH, an 84-amino-acid peptide, is the primary regulator of calcium and phosphorus metabolism in the bone and kidney.[43] The parathyroid gland secretes PTH in response to hypocalcemia to directly increase renal tubular calcium reabsorption and to indirectly enhance intestinal calcium absorption by increasing circulating calcitriol levels.[43] Teriparatide is a recombinant form of PTH composed of only the first 34 amino-acid residues, which constitute the bioactive sequence.[43] Whereas chronically elevated PTH depletes and demineralizes bone, intermittent PTH exposure stimulates bone formation and mineralization because of increased osteoblast activity over osteoclast.[43] Teriparatide is administered as a once-daily SC injection of 20 mcg into the thigh or abdominal wall, with a cumulative lifetime duration of therapy not to exceed 2 years.[36,44]

RANKL Inhibitors

The receptor activator of nuclear factor-kappa B ligand of the RANK receptor (RANKL) is expressed by osteoclasts and their precursors. The interaction between RANK and RANKL modulates bone breakdown via stimulatory effects on osteoclast differentiation, proliferation, and survival.[45] Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor, is the natural inhibitor of RANKL and is primarily expressed by osteoblast-lineage cells under the regulatory control of estrogens.[46] In animal models, OPG deficiency leads to osteoporosis, whereas overexpression results in elevated bone mass.[45] Denosumab is a monoclonal antibody inhibitor (MAOI) of RANKL that antagonizes RANKL activity in a manner similar to that of OPG, thus exhibiting antiresorptive effects.[45] It is indicated for use as an alternative agent in males with ADT-induced osteoporosis, glucocorticoid-induced osteoporosis, or primary osteoporosis, especially those who have failed or cannot tolerate bisphosphonates. Denosumab is administered by a healthcare professional (HCP) as a single-dose SC injection of 60 mg into the upper arm, upper thigh, or abdomen every 6 months. Duration of therapy is typically 5 to 10 years, and treatment carries an associated risk of jaw osteonecrosis and atypical fractures.[36,47]

Sclerostin Inhibitors

Romosozumab-aqqg, the newest agent in the armamentarium for osteoporosis, gained FDA approval for use in postmenopausal women with high fracture risk.[48] However, evidence is limited on its safe and effective use in men with a previous fracture who have failed or cannot otherwise use other agents.[49] This agent is unique in that it is both antiresorptive and anabolic, working to simultaneously build bone and slow bone breakdown. Sclerostin, which is secreted exclusively by osteocytes of mature bone, inhibits the primary metabolic pathway responsible for maintaining bone mass (i.e., osteoblast activity).[50,51] Accordingly, osteocytes reduce the release of sclerostin in response to mechanical or weight-bearing stimuli acting on bone.[51] Romosozumab-aqqg is an MAOI of sclerostin that augments the maintenance of bone mass.[51] It is administered by an HCP as two consecutive injections (105 mg each) once monthly in the abdomen, thigh, or outer area of the upper arm. Therapy duration is limited to 12 months because the anabolic effects tend to wane thereafter. Romosozumab-aqqg carries a black box warning for potential risk of myocardial infarction (MI), stroke, and cardiovascular (CV) death; therefore, this agent should be avoided in patients who have had an MI or stroke within the past 12 months. The risks and benefits of therapy should be weighed in patients with significant CV risk factors.[36,48]

Sex-hormone Replacement

Loss of estrogens and testosterone and other androgens in elderly men contributes to the development of osteoporosis, as these hormones play a critical role in bone formation during development and bone maintenance and remodeling in adults. Androgen deficiency promotes an increase in remodeling characterized by an imbalance between resorption and formation in which osteoclasts' life span is increased and osteoblasts' life span is decreased.[52] Although testosterone therapy in men with osteoporosis has not been clearly defined, its use in testosterone deficiency increases bone density.[53]

Vitamin D Supplementation

The primary role of vitamin D in skeletal health is to facilitate the absorption of dietary calcium and phosphorus. Vitamin D, in the form of calcitriol, acts as a hormone that ultimately serves as a transcription factor for the production of calbindins.[54] Calbindins are calcium-binding proteins that are especially important in the intestinal mucosa for the absorption and transport of dietary calcium and phosphorus. Vitamin D deficiency involves decreased calbindin production and, therefore, reduced calcium absorption. This state leads to increased osteoclast production and mobilization of calcium from bone.[55] If hypocalcemia persists, PTH is released to increase renal reabsorption of calcium and to further stimulate osteoclast production for even more mobilization of bone calcium.

Investigational Therapies

SERMs are standard therapy for female osteoporosis, most notably raloxifene. Although these agents have not been adopted in male patients, results of some small-scale studies suggest the possibility of their use. For instance, raloxifene increases BMD of the hip in men receiving ADT for prostate cancer.[56] Similar to SERMs, selective androgen receptor modulators (SARMs) have been investigated for treating muscle wasting and bone loss.[57] To date, however, no SARM agents have been approved for use.

Lifestyle Modifications

Adequate intake of calcium (1,200–1,500 mg/day) and vitamin D (800-2,000 IU/day) through the diet, supplementation, or both; resistance exercise (i.e., weight-bearing exercise or strength training) at least three times per week; refraining from smoking and drinking excessive alcohol; and fall-prevention strategies (e.g., balance exercises) all serve to strengthen bone in order to prevent or delay loss.[5]

Adequate intake of calcium and vitamin D through the diet, supplementation, or both; resistance exercise; refraining from smoking and drinking excessive alcohol; and fall-prevention strategies all serve to strengthen bone.

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